DE1812906A1 - 4-phenylbicyclo [2.2.2] octane and oct-2-ene-1-carbinols and carboxaldehydes - Google Patents

Description

PATENT LAWYERS

DR.-ING. OF KREISLER DR.-ING. SCHÖNWALD 1812906 DR.-ING. TH. MEYER DRFUES DIPL-CHEM. ALEK VON KREISLER DIPL.-CHEM. CAROLA KELLER DR.-ING. KLDPSCH

COLOGNE 1, DEICHMANNHAUS

Cologne, December 1968 AvK / Ax / Bt

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

4-Phenylbicyclö ^, 2,27octane and -oct-2 ~ en-1-carbinoie

and carboxaldehydes

The invention relates to a new class of compounds namely 4-phenylbicyclo / 2,2,27-ootane and -oct-2-ene-carbinols and carboxaldehydes. The compounds of this class have been found to be useful as anti-fertility agents Prevention of gestation or pregnancy in,. Animals and humans can be used. This effect of the compounds according to the invention is all the more astonishing when you compare the structure of these compounds with the structure compares the contraceptives currently known in medicine.

Currently considered to be the most effective means of preventing pregnancy and gestation are the estrogens and progestins known, being the most commonly used pharmaceutical agents from mixtures of steroids estrogens and progestins exist. When these agents are administered, a sham pregnancy is produced and the Prevents ovulation. To trigger this pseudo pregnancy, these remedies are taken orally during a regular Taken part of every menstrual cycle. Although these compounds are very effective, ingestion can slow down side effects of this particular regimen. The most common side effects are the symptoms similar to those observed during pregnancy. These side effects include nausea, occasionally

0 9 8 2 7/1618

vomiting, mild dizziness, headache, breast enlargement and nipple pigmentation, especially during the first cycle when these agents are taken.

It has been found that 4-phenyl-bicyclo / 2,2,27-octane and -oct-2-en-l-carbinole and -carboxaldehyde used in a completely different way to prevent pregnancy can be. While the estrogen-progestin mixtures, currently most commonly used, taken during relatively long periods of time prior to coitus the compounds according to the invention can be taken after coitus to prevent pregnancy to prevent. The exact mechanism of action is not yet fully understood, but animal experiments recognize that nidation is likely to be prevented in some way.

Except for the striking difference between the compounds according to the invention and known contraceptives In terms of structure, the compounds according to the invention also have a mechanism of action which is different differs significantly from that of the contraception agents currently in use.

This new mechanism of action has numerous practical advantages, e.g. ease of use, elimination taking it over long periods of time, switching it off, taking it according to a certain schedule and avoiding it a constant state of bogus pregnancy that is responsible for numerous side effects.

The invention relates to 4-phenylbicyclo- / 2,2,2 / -octan- and -oct-2-en-l-carbinols and -carboxaldehydes and their use as anti-fertility agents. The connection

0 9 8 2 7/1618

- 3 genes according to the invention have the formula

It says:

A for a single bond or double bond, 0 H ₁ for H, -Ott, -OCH ,, -OC ₂ H ₅ , -OC ₅ H ₇ , - OC ₂₁ H ₉ or RCO-,

R is an alkyl radical having 1 to 12 carbon atoms, and R _{2 is} -CHO or -CHgOR ^, in which

R, is a hydrogen atom, a esterbildender residue of a monobasic acid, for example is an acetyl or propionyl m rest, or a esterbildender residue of a dibasic acid, which is preferably Halbester such hemisuccinyl, Hemiglutaryl or Hemiadipyl is.

0 11

Of the above compounds in which R ^ is R-C-O-, those in which R is an alkyl radical having 1 to 4 carbon atoms are preferred.

The term “phenyl” used in the designation of the compounds according to the invention in this specification means a phenyl radical or a substituted phenyl radical. In compounds in which the phenyl radical bound to the bicyclooc- A tank cage structure is substituted, the substituents are in the p-position to the point of attachment of the phenyl radical to the cage structure. Possible substituents are H, OH, 'OCH. ,, OC ₂ Hc and alkyl carboxylates of p-pheno]. The term "carbinols" used to designate the compounds according to the invention serves as a generic term which includes the carbinols as such and ester derivatives of these carbinols.

909827/1618

Suitable starting materials for the preparation of the compounds according to the invention are correspondingly substituted α-pyrones. In general, these compounds made from acetophenone or substituted acetophenones. The appropriate acetophenone is with diethyl ethoxymethylene malonate treated in ethyl alcohol in the presence of sodium ethoxide under a nitrogen atmosphere. the This intermediate compound formed is cyclized to a pyrone by treatment with anhydrous hydrogen fluoride.

The pyrone is dissolved in an inert solvent such as benzene and heated with ethylene under pressure, the corresponding 4-Phenylbicyclo ^, 2,27oct-2-en-1-carboxylic acid ethyl ester is formed. This ester can be isolated by evaporating the solvent.

The alcohols according to the invention are expediently prepared by a mixture of the corresponding phenylbicyclo / 2,2,2p? ctan- or -oct-2-ene compound, a reducing agent and glyme under a nitrogen atmosphere is heated on the reflux condenser until the reaction has ended. After the mixture has cooled down, the system becomes cautious Water added to decompose the reducing agent. The water is evaporated and the residue in a mixture of water and an inert organic solvent. The organic layer then becomes separated from the mixture, dried and evaporated, the desired phenylbicyclo / 2,2,27octane or -oct-2-en-1-methanol is obtained.

In the above description, the term "phenylbicyclo / ^^ g / octane or -oct-2-en compound" generally used to denote 4-phenyl and substituted 4-phenylbicyclo ^, 2,27octane-1-carboxylic acid, lower alkyl esters of 4-phenyl and substituted 909827/1618

, 2,27octane-1-carboxylic acid, 4-phenyl- and substituted 4-phenylbicyclo / 2,2,27oct-2-ene-carboxylic acid and lower alkyl esters of 4 ~ phenyl and. substituted 4-phenylbicyclo / 2,2,27oct-2-en-1-carboxylic acid.

Lithium aluminum hydride is preferred as the reducing agent for the reaction described above.

The anhydrous ethylene glycol dimethyl ether is used as the solvent for the reaction described above ("Glyme") preferred. Optionally, other readily available suitable solvents can be used instead of "Glyme" can be used in this reaction.

According to another method, according to the invention The carbinols used can also be produced as follows: Phenylbicyolo / 2,2,2_7octan- and -oct-2-en-1-carboxylic acid esters are reduced with sodium in alcohol. When the sodium has dissolved, water is added and the Alcohol evaporated. ' The carbinol is extracted with ether and the ether solution evaporated, with the desired Carbinol is obtained. If the phenyl radical is substituted with a hydroxyl group, the aqueous must of course Mixture must be acidified in order to convert the sodium phenolate into the phenol before extraction with ether.

The ^ -phenylbicyclo / ^ jQig / octane and -oct-2-en-1-carboxaldehydes according to the invention can be prepared as follows; The desired 4-phenylbicyclo _! / 2,2,27-octane or -oct-2-en-1-carboxylic acid and lithium metal are dissolved in methylamine. Ethyl alcohol is then slowly added to this solution and the liquid is evaporated. The residue is dissolved in an amount of water sufficient for solvation, and the resulting solution is acidified and stirred. The precipitate formed becomes 909 827/1618

separated and dried. This precipitation is done in chloroform solved. The chloroform extract is chromatographed on silica using chloroform as the eluent. The ^ phenylbioyclo / S, 2,2_7octane or -oct-2-en-1-carboxaldehyde fraction is collected and cleaned.

The carboxaldehydes according to the invention can also from the Phenylbicyclo / 2,2,2 / 00tan ~ / -oct-2-en-1-carboxylic acid chlorides (produced by treating the corresponding acid with a suitable reagent, such as PClc, POCl 'or SOCIp) getting produced. In a possible process, the acid chloride is mixed with a palladium-on-barium sulfate existing catalyst is hydrogenated with a regulator such as quinoline-sulfur. Another method is that Acid chloride converted to a thiolester by treatment with a mercaptan in pyridine. The thiolester is then treated with deactivated Raney nickel (W-1, refluxed in acetone) to give carb ^ oxaldehyde reduced.

However, if the thiolester is instead treated with a more active Raney nickel catalyst (W-I, W-6) is reduced, the corresponding carbinol is obtained, however, in the case of phenylbicyclo / 2,2,27o.et-2-en-1-carboxylic acid ethylol esters the end product is phenylbicyclo- / 2,2,2_7octane-1-carbinol is obtained.

Example 3;

A mixture of 240 parts of acetophenone and 452 parts of diethyl ethoxymethylene malonate is added dropwise under a nitrogen atmosphere into a flask containing a solution of 50.6 parts of sodium metal in 2000 parts of abs. Contains alcohol. The mixture is stirred for two hours Heated to reflux and then left to cool.

909827/1618

About 1000 to 1500 parts of the alcohol are -under reduced Pressure evaporated, whereupon ether is added in such a quantity that it becomes granular or powdery yellow precipitate forms. The precipitate is filtered off, washed with ether and dried.

The crude yellow precipitation is given at -60 to ⁰ C -7O to · 692 parts of anhydrous hydrogen fluoride. 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 dried then evaporated with dilute NaHCO ^ m solution, dried with anhydrous MgSOh and. The residue is triturated with ethyl acetate, the corresponding 3-carboethoxy-6-phenyl-2-pyrone with a melting point of 107 to 109 ° C. being obtained.

The ^ -Carboäthoxy-o-phenyl ^ pyrone (0.2 mol) is dissolved in 200 ml of benzene and maintained under an ethylene pressure of 1000 atmospheres l6 hours in a suitable pressure vessel at 200 ⁰ C. After the mixture has cooled, the benzene is evaporated off. The residue obtained is ethyl 4-phenylbicyclo- / 2,2,27oct-2-en-1-carboxylate with a boiling point of 192 ° C./12 mm Hg.

If the experiment described in Example 1 using an appropriately substituted acetophenone instead of the acetophenone used in Example 1 is repeated, the desired 4-Arylbicyclo / 2,2,27octan- or -oct-2-en-1-carboxylic acid ester.

9 09827/1618

Example 2

A mixture of 0.03 moles of 4-1
1-carboxylic acid methyl ester, 0.1 mol of lithium aluminum hydride and 150 ml of anhydrous ethylene glycol dimethyl ether (glyme) is refluxed for 4 hours under a nitrogen atmosphere. The mixture is cooled and water is added carefully until the gray lithium aluminum hydride has been converted into a white product. The precipitate is filtered off and washed with anhydrous ethylene glycol dimethyl ether. The filtrate is evaporated and the residue is dissolved in a mixture of benzene and α water. The benzene extract is evaporated and dried with anhydrous MgSOh using 4-Phenylbicyclo-, 2,27octan-l-mettenol is obtained of melting point 78.5 to 79.6 C ^ ^0, which can be recrystallized from methylcyclohexane.

Example 2 A

To a solution of 28.8 g (0.1 mol) of ethyl ^ -Cp-methoxyphenylJbicyelo / i ^ igZoctan-l-carboxy.lat in 350 ml abs. Alcohol turns 23 g (1 g atom) of sodium metal in pieces given. The reaction mixture is first cooled from the outside and then heated to remove all of the sodium to solve φ. The cooled mixture is mixed with 300 ml of water diluted. The alcohol is evaporated off under reduced pressure. The aqueous mixture is extracted with ether. The ether solution is dried with anhydrous magnesium sulfate and evaporated. The residue is made from methylcyclohexane recrystallized, with 4- (p-methoxyphenyl) bicyclo / 2,2,27oetane-1-methanol is obtained which has a melting point of 127 to 128 ° C and is identical to the compound prepared according to Example 4.

90 9 8 2.7 / 1618

IJI I Il ι ι

'■■ "■' ■ - ■■" ■ * "* '' '"' "PIPP!" «I

Example 2 B

4- (p-Methoxyphenyl) bicyclo / 2 _i 2,27oot-2-en-1-carboxylic acid (25.6 g, 0.1 mol) is heated with 50 ml of thionyl chloride for 10 to 15 minutes. The excess thionyl chloride is evaporated off under reduced pressure, with 4- (p-methoxyphenyl) bicyclo ^ / 2,2,27oct-2-ene-lcarboxylic acid chloride being obtained as residue Catalyst composed of 5% palladium on barium sulfate and 0.2 ml of quinoline-sulfur as a regulator (Org. Syntheses, Coll. Vol. III, ■ p. 629), hydrogen is bubbled under normal pressure with stirring. The temperature is gradually increased by external heating until the evolution of hydrogen chloride begins. The neutralization of the escaping gas with aqueous normal alkali shows when the reaction has ended. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. Chromatography on silica with chloroform gives 4 ~ (p-methoxyphenyl) bicyclo / 2,2,27oct-2-en-1-carboxaldehyde.

The catalytic hydrogenation with a catalyst containing 5 $ palladium on activated charcoal becomes 4- (p ~ methoxyphenyl) -bicyclo / 2,22_7octane-1-carboxaldehyde obtain. This compound is made with a mixture of 50 ml of glacial acetic acid and 50 m3. 48 $ aqueous bromine is acidic for 4 hours heated to reflux under a nitrogen atmosphere. The mixture is cooled and poured into water. The precipitate is dried and recrystallized from xylene, whereby 4- (ρ-hydroxyphenyl) bicyclo / 2,2,27oct-2-en-1-carboxaldehyde from melting point 154 to 155 ° C is obtained.

909827/1618

- ίο -

Examples ^ to 6

The experiment described in Example 2 is repeated, however, an equivalent amount of the compounds listed below in place of that in Example 2 is used 4-phenylbicyclo / 2Y2,2 / 'octane-1-carboxylic acid methyl ester is used and the alcohols mentioned below are obtained.

Example starting material alcohol game -

3 4- (p-Methoxyphenyl) bi- 4- (p-Methoxyphenyl) bicyclocyclo _j / 2 _i 2.2 / octane-1- ^, ^, ^ octane-1-methanol, ^ carboxylic acid melting point 127 to 128 ° C

4 4- (p-Methoxyphenyl) bi- 4- (p-methoxyphenyl) bicyclocyclo / ^ 2.2 / octane- _{1- / 2.2 J} 2j7octane-1-methanol, _Q aryl carboxylate, melting point 127 to 128 ° C

5 4- (p-Ethoxyphenyl) bi- 4- (p-ethoxyphenyl) bieyclocyclo / 2,2,2 / oct-2-en- / 2,2,2 , 27oct-2-en-1-methanol, 1-carboxylic acid ethyl ester

6 4- (p-hydroxyphenyl) bi- 4- (p-hydroxyphenyl) bicyclocyclo / 2.2.2 / ootane-1- / 2.2.2 / octane-1-methanol. carboxylic acid melting point 202 to 204 C.

Example 7

5 ml of acetic anhydride are added to a solution of 2.46 g of 4- (p-methoxyphenyl) bieyeIo- / 2,27octane-1-methanol in 50 ml of dry pyridine. The solution is left to stand for ΐβ hours. After adding 5 ml of water, the solution is left to stand for 4 hours. The solution is poured into a mixture of 200 g of ice and 200 ml of βη-HCl. When the ice has melted, the precipitate is filtered off, washed well with water and dried to give 4- (p-methoxyphenyl) bieyclo ^, 2,27octane-1-methanol acetate. By recrystallizing the ester from alcohol, crystals with a melting point of 105 to 106 ° C. are obtained.

909827/1618

- li -

Examples 8 to 14

The experiment described in Example 7 is used of the starting alcohols and acid chlorides or acid anhydrides mentioned below repeated, the specified products can be obtained.

In-alcohol
game

4-phenylbicyclo- / 2,2.2 / octane-1-methanol

4- (p-Xthoxypheny3) -1-methanol

4- (p-Methoxyphenyl) bicyclo / 2,2,27oct-2-en-1-methanol

4- (p-methoxyphenyl) -bicyolo / 2,2,27octane-1-methanol

4- (p-hydroxypheny]> 1-methanol

4- (p-hydroxyphenyl) -1-methanol

4- (p-hydroxyphenyl) -

Acid chloride anhydride or product

en-1-methano

Acetic anhydride

Dodecanoxyl chloride

Succinic anhydride

Adipyl chloride

Acetic anhydride

Propionyl chloride

Isobutyryl chloride 4-phenylbicyclo- / 2,2.2 / octane-1methanolacetic acid ester

4- (p-Ethoxyphenyl) bicyclo / 2,2,27octane-1-methanol-dodecanoic acid ester

4- (p-methoxyphenyl) -

y ^^ en-1-methanoT-succinic acid monoester

4- (p-Methoxyphenyl) -bioyclo / 2,2,27octane-1-methano / adipic acid monoester

4- (p-AcetoxyJahenyl) bicyclo ^, 2,27octane-1-methanol acetic acid ester

4- (p-Propionoxyphenyl) bicyclo / 2.2.2 / octane-1-methanolpropionic acid ester

4- (p-Isobutyrox2; -. Phenyl) bicyclo / 2.2, j oct-2-en-1-methanol isobutyric acid ester

Acylation of the phenolic hydroxyl group can be carried out in the manner described below.

09827/1618

Example 15

A solution of 2.46 g of 4- (p-hydroxyphenyl) bicyelo- / 2 ^ 2.27octane-1-methanol in 50 ml of pyridine is in the manner described in Example 7 with 0.10 mol of acetic anhydride treated, whereby 4- (p-acetoxyphenyl) bicyclo- / 2,2,2700tane -! - methanol is obtained.

Example l6

A solution of 2.46 g of 4- (p-hydroxyphenyl) bicyclo- / 2,2,27octane-1-methanol in 50 ml of pyridine is treated with 0.10 mol of propionyl chloride in the manner described in Example 7, with 4- ( p-Propionoxyphenyl) bicyclo- / ß., 2.27octane-1-methanol is obtained.

Example 17

A solution of 3.16 g of 4- (p-acetoxyphenyl) bicyclo- / 2.27octane-1-methanol acetic acid ester and 1.8 g of potassium carbonate in 100 ml of 90% ethanol is refluxed for 16 hours. The resulting solution is cooled, poured into ice water and acidified with hydrochloric acid. The precipitate is filtered off, washed with water and dried, the acetic acid ester of 4- (p-hydroxyphenyl) bicyclo- / 2.27octane-1-methanol being obtained.

Example l8

J) g of lithium metal are added to a solution of 12.9 g of 4- (p-methoxyphenyl) bicyclo- / 2,2,27oct-2-en-1-carboxylic acid in 300 ml of methylamine. After the lithium has dissolved, 100 ml of alcohol are added dropwise to the solution. The solution is evaporated. The residue is dissolved in 250 ml of water and then acidified with 150 ml of 6N HCl. The mixture is stirred for one hour. The precipitate is filtered off, washed with water and dried. The residue will

triturated with chloroform and the extract on silica 9098 2.7 / 1 6

chromatographed with chloroform as the eluent. A fraction is obtained which, based on the infrared spectrum / 2.9 / U (OH), 5.7 αχ (aldehyde CH), 5.89 (aldehyde C = O) / and the nuclear magnetic resonance spectrum / (CDCl ,, 0, 12 t - (1H, singlet - aldehyde CH), 2.92fc (4H, quadruplet J «-» 15 Hiz-p-disubstituted benzene), 3.45 £ (2H, doublet J ^ le / f & - olefinic protons) , £ 4.20 (IH, singlet phenolic QH group), 8.00 - 8.55 ^ (8 H - aliphatic protons) _7 as 4- (p-hydroxyphenyl) bicyclo / 2,2,27oct-2-ene -1-carboxaldehyde is identified. By recrystallization from xylene, crystals with a melting point of 154 to 155 ° C. are obtained.

By repeating the experiment described in Example 18 using 4- (p-methoxyphenyl) bicyclo- / 2,2,27octane-1-carboxylic acid instead of the 4- (p-methoxyphenyl) bicyclo / 2,2,27oclt-2-en-l- used in Example l8 - The carboxylic acid is 4- (p-hydroxyphenyl) bicyclo- / 2,2,27octane-1-carboxaldehyde obtain.

Example 18 A

A solution of 29 g (0.1 mol) of the 4- (p-methoxyphenyl) bicyclo / 2,2,27oct-2-en-1-carboxylic acid chloride3 prepared in the manner described in Example 2B is reacted with 12 for 16 hours , 4 g (0.2 mol) ethanethiol in 50 ml Λ

Leave to pyridine. The solution is poured into a mixture of 200 ml of 5N HCl and 200 g of ice. The mixture is with Dichloromethane extracted. The dichloromethane solution is dried and evaporated, the Ä'thylthiolester von 4- (p-methoxyphenyl) bicyclo / 2,2,27oct-2-en-1-carboxylic acid is obtained.

A suspension of 500 g of W-I Raney nickel (H. Adkins, "Reactions of Hydrogen with Organic Compounds Ovwr Copper-Chromium Oxide and Nickel Catalysts, "the University of Wisconsin Press, Madison, Wis., 1937, p. 20) becomes two

909827/1618

Heated under reflux for hours. The thiolester in 500 ml in acetone is then added with stirring whereupon a is refluxed for a further hour. The catalyst is filtered off and the Piltrat evaporated, with 4- (p-methoxyphenyl) bicyclo / 2, 2,; 27oct-2-en-1-carboxaldehyde is obtained.

Example 18 B

By repeating the experiment described in Example 18A using W-6 Raney nickel instead of W-1-Raney nickel becomes 4- (p-methoxyphenyl) bicyclo / 2,2,2_7- ' Octane-1-carbinol with a melting point of 127 to 128 ° C was obtained.

Example 19

A solution of 0.01 mol of 4- (p-hydroxyphenyl) bieyeIo- / 2,27octane-1-carboxaldehyde, 0.02 mol of sodium methoxide and 0.02 mol of dimethyl sulfate in 50 ml of methanol is refluxed for 16 hours. The solution is cooled and then poured into 400 ml of 5% aqueous NaOH. The precipitate formed is filtered off, washed with water and dried, with 4- (p-methoxyphenyl) bicyclo / 2,2,2 / octane-1-carboxaldehyde being obtained.

Example 20

A solution of 0.01 mol of 4 (p-hydroxyphenyl) bicyclo- _/ / 2.2.27oct-2-en-1-carboxaldehyde, 0.02 mol of sodium methoxide and 0.02 mol of diethyl sulfate in 50 ml of methanol is 16 hours on Heated to reflux. The solution is cooled and then poured into 400 ml of 5% aqueous NaOH. The precipitate formed is filtered off, washed with water and dried, with 4- (pA "thoxyphenyl) bicyclo / 2,2,2 / octane-1-carboxaldehyde being obtained.

9 0 9 8 2 7/1618

Examples 21 and 22

The experiment described in Example 7 is repeated, except that the hydroxy compounds listed below in place of 4- (p-methoxyphenyl) bicyclo / 2 ^ 2,27octan-1-methanol, and the acid anhydride or acid chloride in place of said Essigsäur used in Example ¹ J anhydrids are used. The specified esters are obtained here.

Example hydroxyl acid ester game compound hydride or

-chloride

21 4- (p-hydroxyphenyl) - acetic 4- (p-acetoxyphenyl) - bicyclo ^ ™, 2,27octan- reanhy- bicyclo _J / ^, 2,27octan ~ 1-carboxaldehyde drid 1-carboxaldehyde

22 4- (p-Hydroxyphenyl) -propio-4- (p-Propionoxybicyclo / 2,2,270 ^ -2-nylchlophenyl) -bicycloene-1-carboxaldehyde rid / 2.2.2 / octane-carboxaldehyde

The compounds according to the invention can be used for prevention pregnancy and gestation according to the method according to the invention in any suitable manner administered. For example, administration can be parenteral, i.e. subcutaneous, intramuscular or intraperitoneal take place. Oral or rectal administration is also possible. j |

In most animals, these compounds are effective when given in a single dose before the estimated time the implantation of the fertilized egg. It is also possible to use these compounds with equal effectiveness to be given in divided doses after mating for a period of 2 to 6 days. These connections can can therefore be administered in single doses or divided doses up to the 15th day after coitus.

909827/1618

The compounds according to the invention are preferred administered after coitus but before the estimated time of implantation of the fertilized egg in the uterus.

The given dose depends on the age and the state of health and the weight of the recipient as well as the frequency the administration. In general, the dose of 0.001 to 50 mg of active ingredient per kg per day is the desired Result achieved. A dose of 0.005 to 10 mg / kg per day is preferred and a dose in the range of 0.01 to 5 mg / kg per day are particularly preferred. .

Excellent results in preventing the pregnancy of rats have been obtained with these compounds, as the following example shows. The procedure according to the Invention can therefore in addition to the previously known Methods of combating rodents or as a substitute for these methods are used.

Example 23 .

In immature rats, premature puberty is induced with a single dose of gonadotropin of the serum from pregnant mares, and the animals are mated with normal male rats. A suspension of 4- (p-methoxyphenyl) -blcyclo ^^ i ^ TOctane-1-methanol-acetic acid ester in sesame oil is administered orally daily for a period of 6 days, starting on the day on which sperm or a vaginal plug is detected . One week after mating, the animals are sacrificed and their uteri examined for implantation sites. If such spots are found, the animal is considered pregnant. The comparison animals have an average of 8 implantation sites. The dose at which 50% of the animals show no sign of pregnancy, the EDc ₀ , is calculated to be 0.31 mg / kg / day.

909827/1618

The experiment described in Example 2j5 is repeated, but using 4- (p-methoxyphehyl) bieyclo _z / 2,2,2_7octane-1-methanol instead of the compound used in the experiment described above. An ED ₀ in the range from 0.31 to 1.24 og / kg / day is found.

The experiment described in Example 23 is repeated er.ieut, but using 4 ~ (ρ-hydroxyphenyl) bioyclo / 2% 2,2y ^r oct-2-en-l-carboxaldehyde instead of used in the above test compound. A Q ranging from 0.31 to 1.24 mg / kg / day is found.

An experiment in which a compound according to the invention is given in a single dose is also carried out. The experiment described above is repeated with the difference that the compound according to the invention is administered orally in a single dose to female rats on the third day, about 53 hours after mating. If 4- (p-methoxyphenyl) bicyclo / 2,2,2y ^r octane-1-methanol is given as active ingredient in this way, the EDj-q is calculated to be 0.90 mg / kg / day.

The compounds according to the invention can also be used with good results in preventing pregnancy in other experimental animals, e.g. mice, guinea pigs and ka rabbits, and are also effective in preventing pregnancy in domestic animals such as cows, sheep and Horses. In small animals it is usually convenient to take the compounds according to the invention orally in the form of tablets or to give capsules or to add to the feed. In the case of large animals, on the other hand, it is often useful to use them to be administered parenterally.

The active ingredients according to the invention can be used in preparations according to the invention, e.g. tablets, capsules, powder packs or liquid solutions, suspensions or

909827/1618

E3.exieren can be used 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. In these preparations, the active ingredient is usually always in an amount of at least 0.01 wt -.%, Based on the total weight of the preparation, and not more than 90 wt -.% Present.

In addition to the active ingredient 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 from about 1 to 50 wt -.% ■ 4-Phenylbieyclo- / ß, 2,27octan- or oct-2-en-l-carbinol or -carboxaldehyds according to the invention and 99 to 50 wt .- $ of an Carrier. In another embodiment, the active ingredient is tabletted with or without excipients. In a further embodiment, the active ingredient is incorporated into powder packs and used. These capsules, tablets and powders usually consist of about 0.5 to 95 $ i preferably 1 to 50 wt -.% Of the active ingredient. These preparation forms preferably contain about 0.5 to 25 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, are suitable as pharmaceutical carriers and oils of animal, vegetable or synthetic origin, e.g. EHfcU oil, soybean oil, mineral oil and sesame oil. In general, water, saline, aqueous dextrose (glucose) and related sugar solutions and Glycols, e.g. propylene glycol or polyethylene glycol, as liquid carriers preferred, especially for injection

9 0 9827/1618

solutions. Sterile injection solutions, e.g. in saline solution, usually contain about $ 0.05 to $ 25 * preferably about 0.1 to 5% by weight of the active ingredient.

As already mentioned, oral administration can be in a suitable suspension or in a syrup, in which the active ingredient is usually contained in an amount of about 0.01 to 5%, preferably about 0.02 to 1% by weight. In the case of these preparations, the pharmaceutical carrier can be an aqueous carrier, for example an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are set out in "Remington's Practice of Pharmacy "by E.W. Martin and E.F. Cook, a well known handbook in the field.

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

Example 24

A large number of unit capsules are prepared for oral administration, in-which the mg weigh about 25 standard two-piece hard gelatin capsules,-2-en 7oct with 50 mg of powder-% verförmigem 4- (p-methoxyphenyl) bicyclo ^, 2, £ -lmethanol, 125 mg of lactose and 1 mg of finely divided silica ("Cab-o-sil") are filled.

In addition to the lactose in the above-mentioned preparation or in its place, fillers, such as anhydrous lactose, kaolin, precipitated potassium carbonate, Mannitol, microcrystalline cellulose or the like can be used with good results.

909827/1618

If necessary, lubricants * such as talc, magnesium stearate, Calcium stearate, Mayo starch, stearic acid, polyethylene glycol 4000 or the like, instead of the silica "Cab-o-sil" with good results in that in Example 24 described preparation can be used.

Example 25

A large number of unit capsules are available for oral use Administration made by soft gelaxitine capsules with a solution of 4- (p-hydroxyphenyl) bicyclo / 2,2,2 / -octane-1-methanol-dodecanoic acid ester be filled in sesame oil.

Example 26

A large number of tablets are conventionally prepared so that the dosage unit contains 10 mg of active ingredient, 5 mg of gelatin, 1.5 mg of magnesium stearate and 100 mg of lactose. Slow release tablets can also be made by applying suitable coatings. In other tablet formulations, the tablets can contain 1 to 7% (based on the total weight) of a lubricant such as talc, silica "Cab-o-sil" and stearic acid instead of the magnesium stearate in the composition described above.

As a further binding agent that is used instead of the gelatin in The preparation described above can be used, starch, ethyl ellulose, polyethylene glycol 4000 and the like instead of the lactose in that described above Other fillers, e.g. anhydrous lactose, mannitol, microcrystalline cellulose can also be used in the formulation and the like., can be used.

9098 27/1618

In certain recipes, a typical disintegrant, e.g. methyl cellulose, Veegum, Starch, microcrystalline cellulose and the like are used.

Example 27

A parenteral preparation that can be administered by injection is prepared by stirring 0.5 wt .- ^ 4- (p-hydroxyphenyl) bicyclo / 2 ^ 2.27octane-1methanolacetic acid ester in sterile mineral oil.

Example 28

Suppositories for rectal use can be prepared by stirring 0.25 wt .- ^ 4- (p-hydroxyphenyl) -bicyclo / ^^ eiToctane-1-methanol 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 prepared using other compounds according to the invention, those above have been specifically mentioned but are not intended to be limited thereto. The connections are made in the specified amounts are used according to known methods described in the above-referenced Martin and Cook manual are.

909827/1618

Claims (1)

1812 * 306 Claims 1.) Compounds of the general formula where A is a single or a double bond, It RH, OH, OCH ,, OC ₂ H ₅ , OC ₃ H ₇ , OC ^ Hq or RCO-, where R is an alkyl radical of 1 to 12 carbon atoms, and Rp is CHO or CHpOR ,, where R., hydrogen or a Is monoester of an ester-forming pharmaceutically acceptable mono- or dibasic acid residue. t! 2.) Compounds according to claim 1, wherein R.,. H, -C-CH - ,,, 0 3-5 -C-CHpCH ^, hemisuccinyl, hemiglutaryl, or hemiadipyl is. 3 ·) 4- (p-Methoxyphenyl) bicyclo ^ 2, 2, i ^ octane-1-methanol. 4.) 4- (p-Hydroxyphenyl) bicyclo ^ 2.2, g7octane-1-methanol. 5.) $ -Phenylbicyclo _< / 2,2,27octane-1-methanol. 6 ·) ² f - (p-Methoxyphenyl) bicyclo ^, 2,27octane-1-methanol acetic acid ester. 7.) 4- (p-Hydroxyphenyl) bicyclo ^ 2,2,27octane-1-carboxaldehyde. 8.) 4- (g-lt3loxyphenyl) bicyclo _< / 2,2,27octane-1-carboxaldehyde. 909827/1618 1 8 1 2 β Ο 9.) Contraception means characterized by a content of
a) one or more compounds of claims 1 to and b) a pharmaceutically acceptable diluent or carrier. lo.) procedures for preventing the pregnancy of animals, characterized in that the female animals are given an effective amount of one or more compounds of claims 1 to 9 administered. 11.) Process for the preparation of compounds of the general formula where A is a single or double bond, ti R _{1 is} H, OH, OCH _{1, OC 2} H ₅ , OC ₃ H ₇ , OC _{21 -H 9} or RCO-, where R is an alkyl radical of 1 to 12 carbon atoms, and R ₂ CH ₂ OR, where R is hydrogen. » an ester-forming radical of a monobasic acid, for example an acetyl radical or propionyl radical, or an ester-forming radical of a dibasic acid which preferably forms half-esters, for example hendsuccinyl, hemiglutaryl or hemiadipyl, is characterized in that a compound of the general formula 909827/1618 * - 24 - wherein A and R _{1 are} as defined above and Rp is COOH or COO alkyl, reduced. 12.) Process for the preparation of compounds of the general formula CHO where A is a single or double bond, and RH, OH, OCH ,, OC ₂ H ₅ , OC ₃ H ₇ , OC ^ H ₉ or RCO-, where R is an alkyl radical of 1 to 12 carbon atoms, characterized in that one is a compound of the formula COOH wherein A and R are as defined above, 1. Treated with lithium metal in methylamine, then slowly adding ethyl alcohol, the residue in water dissolves and acidifies, whereby the desired Carbox * aldehyde precipitates, 2. treated with PCIc, POCl, or SOCl ₀ and that 5 ? 2 Acid chloride is converted into the corresponding carboxaldehyde by a) hydrogenation of the acid chloride with a catalyst, such as palladium on barium sulfate, in the presence a regulator, such as quinoline-sulfur, or 909827/1618 b) Reacting the acid chloride with a mercaptan in pyridine to a thiolester, which is deactivated with Raney nod! is reduced. 909 8 27/1618