DE1812889A1 - 4-Phenylbiciclo [2.2.2] octane and -oct-2-en-1-carboxamides - Google Patents

Description

PATENT LAWYERS 1P1? FifiQ

DR.-ING. BY KREISLER DR.-ING. SCHÖNWALD ' ^ö ' ^{L ö ö b} DR.-ING. TH. MEYER DR. FUES DIPL.-CHEM. ALEK VON KREISLER DIPL-CHEM. CAROLA KELLER DR.-ING. KLOPSCH

COLOGNE 1, DEICHMANNHAUS

Cologne, November 19, 1968 / Ax / Hz

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

4-Phenylbicyclo / -2,2,2-7 ° ^{ctane and} -oct-2-ene-lcarboxamides

The invention relates to a new class of compounds, namely 4-phenylbicyclo [2,2,2 ^ joctan- and -oct-2-en-i-carboxamides and their derivatives. The term "phenyl" in the general designation of the compounds according to the invention includes phenyl and substituted phenyl. In compounds in which the phenyl radical is substituted, the substituent is in the p-position to the point of attachment to the ßicyclooctankäagestruktur. These substituents can be groups such as H, OH, their alkyl carboxylates, OCH, and OC ₂ Hc.

It should also be noted that the term "carboxamides and their derivatives" means the carboxamides, hydrazides and hydroxamic acid derivatives which are specifically defined below.

It has been found that the compounds of this class can be used as contraceptives. These The effect of the compounds according to the invention is all the more astonishing when these compounds are structurally be compared with contraceptives currently in known in medicine.

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The agents that are known to be the most effective contraceptives are compounds such as estrogens and Progestins. Of these pharmaceutical agents will be currently most frequently used mixtures of steroids, estrogens and progestins. Taking these funds causes a pseudo pregnancy and prevents ovulation. To this state of bogus pregnancy To trigger, these agents are administered orally during a regular portion of each menstrual cycle. she are very effective, however, this dosage regimen can cause side effects. The most common The side effects that occur are similar to symptoms seen during pregnancy. to These side effects include nausea, occasional vomiting, mild dizziness, headache, breast enlargement and pigmentation of the nipples »These side effects are most commonly seen during the first cycle in which these funds are taken.

It has been found that 4-phenylbicjoloC2,2,2 '] -octane and -oct-2-en-i-carboxamides can be used in a completely different way to prevent pregnancy. While the estrogen-progestin mixtures currently most frequently used have to be taken for a reasonably long time before coitus, the 4-phenylbicycloQ?, 2, 2] octane and oe '- 2-en-1 »Carboxamides can be used before or after coitus to prevent pregnancy. The exact mechanism of action has not yet been fully clarified, but animal experiments show that it is most likely that nidation is prevented in some way «

Besides the striking structural difference in the joints according to the invention compared to known contraceptives thus also shows that the compounds according to the invention have a mechanism of action that differs significantly from the contraceptives used so far »QfiQft? 7 / 1f) 17

This new mechanism of action has numerous practical advantages, such as ease of use, avoidance of long-term ingestion, avoidance of a specific schedule and avoidance of a permanent state of pseudo-pregnancy, which is responsible for numerous side effects.

The compounds according to the invention have the formula

■ A- ^ 2

Herein , A is a single bond or a double bond; A ₁ germ «Ir H, -OH, -OCH ₅ , -OC ₂ H ₅ , -OC ₅ H ₇ , -OC ₄ H ₉ or 0

HCO-, where R is an alkyl radical with 1 to 12 carbon atoms, and R ₂ can be -NH-NH ₂ , NHOH,

■ -Rjj and IQiNw stand, in which R ,, R ^, R ₅ or Rg water, CH, or CgH »can be or R-. and R ₄ as well as R ~ IS and R ^ SUSSNMm can form the following ring systems with the nitrogenι pyrrolidino, piperidino or morpholines

Of the above-mentioned compounds in which R « 0

for RCO- , compounds are preferred in which It is an alkyl radical of 1 to 4 carbon atoms. Particularly preferred are compounds according to the invention of the formula above, in which A can be a single bond or a double bond, R ₁ can be HO-, HJCO-, HeC ₂ O- or CH, C0 ₂ - and R _{2 can be} NH ₂ stands.

The invention further relates to a method for preventing pregnancy, which is characterized in that the female animal is administered an effective amount of one or more compounds of the formula (I).

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The invention further encompasses pharmaceutical preparations which contain an effective amount of one or more compounds of formula (I) in combination with customary pharmaceutical diluents or extenders contain · the subject the invention is also the process for the preparation of the compounds of formula (I).

The term ^ -phenylbicyclo / S ^ j ^ zoctane and -oct-2-en-1-carboxamides is used as a generic term and includes 4-phenylbicyclo / S, 2,2_7octane-1-carboxamides, 4- (p-subst. Phenyl) bicyclo / 5.2 ₁ 27oetane-1-carboxamide, 4-phenylbicyclo ^, 2, ^ 7octane-1-carbohydroxamic acids, 4- (psub st. Phenyl) bicyclo ^ 2,2, 27oc tan-1 -carboxylic acid hydrazide and the corresponding "bicyclo / S, 2,27-oct-2-en ^M compounds. In this definition, the term" substituted phenyl "includes a phenyl radical whose p-water

substance by groups such as -OH, -OCH ,, 0 °

-OC ₄ H ₉ or -OCH, in which E is an alkyl radical having 1 to 12 carbon atoms, has been replaced.

A suitable starting material for the compounds according to the invention can be starting from acetophenone or a substituted acetophenone can be produced. The desired acetophenone is made with diethyl ethoxymethylene malonate treated in ethyl alcohol in the presence of sodium ethoxide under a nitrogen atmosphere. The so educated Intermediate compound 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 / 5,2,27oct-2-en-1-carboxylic acid ethyl ester is formed. This ester then becomes the corresponding 4-phenylbicyclo / 2 ", 2,2 / oct-2-en-1-carboxylic acid hydrolyzed.

The carboxamides according to the invention can be prepared

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can be created by using a
or -oct-2-en-1-carboxylic acid heated to reflux with thionyl chloride and this mixture is then added to an aqueous solution of the corresponding amine, the desired carboxamide being precipitated. This carboxamide can be separated off and purified from the reaction mixture by customary methods.

The carboxamides can also be prepared by heating the desired 4-phenylbicyclo / ^^ SToctane or -oct-2-en-1-carboxylic acid ester with the desired amine in an autoclave in the presence or absence of an inert solvent. Here, temperatures are preferably from 150 to 23O ⁰ C.

The carboxamides produced in this way have the formula _n

II.

Stand in it

A for a single bond or a double bond, 0 R ₁ for H, OH, OCH ₅ , -OC ₂ H ₅ , OC ₅ H ₇ , -OC ₄ Hq or RCO-, where R is an alkyl radical with 1 to 12 carbon atoms,

R, for hydrogen, a methyl radical or ethyl radical, Rq_ for hydrogen, a methyl radical or ethyl radical, and R, and R ^ together with the nitrogen atom can do that form the following ring system:

Pyrrolidino,
Piperidino or
Morpholino.

The hydroxamic acids according to the invention can be prepared as follows: A ^ - Phenylbicyclo / Ü ^ j ^ octan- or -oct-2-en-1-carboxylic acid is treated with thionyl chloride. This mixture is 1 hour at room temperature

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touched. The solution is evaporated under reduced pressure and the residue is dissolved in pyridine. To this Solution is given a solution of a hydroxylamine in pyridine. The resulting mixture will be 15 "to 25 hours stirred, and the desired 4-phenylbicyclo / ^^ j ^ / octane or -oct-2 ^ en-1-carbohydroxamic acid is precipitated in which the reaction mixture is poured into an ice-cold acid, e.g. hydrochloric acid. This precipitation is then after the usual methods separated and purified.

The hydroxamic acids made in this way have the formula

III. RA \ % ^

in which A and R ^ have the meanings given above.

The carboxylic acid hydrazides according to the invention can conveniently be prepared as follows. One starts with the desired lower alkyl ester of 4-phenylbicyclo / ^^ j ^ / octane or -oct-2-en-1, dissolved in a suitable inert solvent such as amyl alcohol -carboxylic acid from. The desired hydrazide is added to this solution and the mixture is refluxed for about 72 hours. The product is concentrated under reduced pressure and the hydrazide formed ~. The residue was recrystallized from toluene. In the context of the description, lower alkyl radicals are alkyl radicals with 1 to 4 carbon atoms.

The carboxylic acid hydrazides prepared in this way have the formula

IV. R, - / ~ \ / ³ V f °

Here A and R ^, have the meaning given above, and Rc stands for hydrogen, GH, or R _c for hydrogen, CH-, or C ₀ Ht-,

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R ₁ - and Rg can form the following hanging systems together with the nitrogen:

Pyrrolidino, Piperidino or Moxpholino.

In the following examples, parts are parts by weight, unless otherwise specified

example 1

A mixture of 5 parts of thionyl chloride and 1 part of 4-Pheaiylbicyolo ^ ei, 2,27octane-1-carboxylic acid is refluxed for 15 minutes and then cooled. This solution is poured into cold stirred aqueous ammonium hydroxide. Here, a precipitate forms, which abfiltrjatft, washed with water and air dried to give 4-phenylbicyclo / is 5,2,2 / octane-1-carboxamide 5 obtained of melting point 229 to 232 ⁰ * C.

Example 1-A

A mixture of 28.8 g (0.1 mol) 4- (p-methoxyphenyl) bioyülo /? ₍ 2, ^ octane-1'-carbonic acid ethyl ether and a vane ™ & 15 »5 β (0.5 mol) methylamine in 100 ml alcohol is placed in a 400 ml autoclave. The mixture is ^{kept at 200 °} C. for 16 hours. The mixture is cooled and evaporated to a residue. By recrystallization of the bridging tandes from ethyl acetate, N-methyl-4- (p- methoxyphenyl) bicyclo / 2,2,27octane-1-carboxamide rom Melting point 204 to 204.5 ° C obtained with the according to Example 3 obtained product is identical.

Examples 2 to 7

The experiment described in Example 1 is repeated, but using equivalent amounts of the acid specified below instead of the 4-phenyl-bi'cyclo ^ 2,2,27octane-1-carboxylic acid and an aqueous solution of the specified amine

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18128

can be used in place of the ammonium hydroxide solution used in Example 1. You will be the following products obtain:

At game

acid

Amine

product

4- (p-Methoxyphenyl) bicyclo ^ S, 2, 2 / octane-1-carboxylic acid

4- (p-Methoxyphenyl) bicyclo ^ S, 2,27octane-1-carboxylic acid

4- (p-Methoxyphenyl) -bieyclo / 5,2, ^ oc tan-1-carboxylic acid

4- (p-Methoxyphenyl) -bicyelo / 2,2,27octane-1-carboxylic acid

- Ammonia 4- (p-Hethoxyphenyl) -bicyclb / 2,2,2 / octane-1-carboxamide. 235.5 to 236 ⁰ C.

Methyl-N-methyl-4- (p-M «thoxy ^ amine phenylV-bicyclo

/ 2,2,2 / octane-1-carboxamide, 204-240.5 ° 0 di- N, N-dimethyl-4- (pmethyl-methoxrphenyl) bicycloamine / 5,2,27octaa-1-carboxamide, 138-140 , 5 ^ C pyrro- N _t N-rT * tramethyl «n-4-lidine (pm« thoxyphtnyl) -

bicyclo / 5.2.2 / octane-1-carboxamide

4- (p-M «t bicyeloj __ 1 -carboxylic acid

enyl) -ootan-

4- (p-Methoxyphenyl) bicyclo ^ S, 2.2 / octane-1-carboxylic acid

Pi- Ν, Κ-Pentamethylene peridin 4- (p-methoxypk * nyl) -bicyolo ^ S, 2 _t g7oc tan · 1-carboxamide

Mor- N, N-3'-0xa-pentapholin methylene-4- (p-methO3 phenyl) bicyclo ^ 5,2,2 ο c t an-1 -carb onic acid eamide

Example 8

10 parts of 4- (p-ethoxyphenyl) bicyclo / 5,2,7oct-2-en-1-carboxylic acid ethyl ster

and 50 parts · Anhydrous ammonia are placed in an autoclave · The mixture is kept for 16 hours with shaking at 160 ° C under the autogenous pressure. The mixture is cooled and excess ammonia evaporated, with 4- (p-lthoxyphenyl) bicyclo / 5.2, ^ 7oct-2-en-1 -carboxamide remaining as a residue.

40 Examples 9 and 10

The experiment described in Example 8 is repeated, but using an equivalent amount of that given below Ester instead of 4- (p-ethoxyphenyl) bicyclo- ^ 2 \ 2.27oct-

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2-en-1-carboxylic acid ethyl ester and an equivalent amount of the specified amine can be used in place of the ammonia used in Example 8. The below mentioned Products are received.

Partial acid amine product

9 4 ~ (p-hydroxyphenyl) - ammonia 4- (p-hydroxyphenyl) -bil / Z ^^ bil ^^ g / t

y / ^ j ^ y ^^ jg

1-carboxymethyl-1-carboxamide ester

10 4- (p-hydroxyphenyl) - methyl- N-methyl-4- (p-hydroxy-

bicyclo / ^^ jg / oct ^ - amine phenyl) bicyclo / 2,2,2 / -

en-1-carboxylic acid oct-2-ene-i-carboxylic acid

methyl ester amide

Example 11

To a solution of 0.010 mol of 4- (p-hydroxyphenyl) bicyelo- / JZ ₁ 2.27oc tan-1 -carboxamide

in 50 ml of anhydrous pyridine is at least 1 molar Given equivalent of acetic anhydride. The solution is left to stand for 16 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 6N HCl. When the ice has melted, the precipitate is filtered off, washed with water, dried and used as 4- (p-Acetoxyphenyl) bicyclo ^ 2 ", 2,27octane-1-carboxamide identified.

Examples 12 and 13

The experiment described in Example 11 is repeated, but with the following reactants instead of 4- (p-hydroxyphenyl) bicyclo / 2,2,27octane-1-carboxamide and in place of the acetic anhydride used in Example 11, the products mentioned below can be obtained.

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At- acidiel carboxylic acid amide chloride product

4- (p-hydroxyphenyl) - Pro- 4- (p-propionoxyphenyl)

il / 2227 i il ^ 2227

(pHyypy) (ppinxyphnyl)

bicyclo / 2,2,27OCtOn-pionyl- t> icyclo ^ 2,2,27octan.-1-1-carboxamide Chloride carboxamide

15 N-methyl-4- (p-hy- ηοτ1- y (p

droxyphenyl) bicyclo-? {i; "., noyloxyphenyl ^ icyclo-

/ 2 \ 2.27oct-2-en-1- ^{CMon <l} ^ 2.2 / oct-2-en-1-ear-

carboxylic acid amide

^ O if the esterification of the phenolic p ~ hydroxyl group is desired this can, as the above examples show, be achieved by either the appropriate Acid chloride or acid anhydride 4iliBii <Ml », where equally good results are obtained »

Example 14

A solution of 2.6 parts of 4- (p-met3ao3qrplienyl) -bicyclo- / 2,2,27octane-1-carboxylic acid in 30 parts of Bssol is treated with 5 parts of thionyl chloride and stirred for 1 hour. The solution is evaporated under reduced pressure. The residue is dissolved in 20 parts of Pyricliai. After adding a solution of 6.9 parts of hydrosrillaaisihydrochloride in 20 parts of pyridine, the mixture is stirred for 16 hours. The mixture is in a mixture του. ^c 00 SeiLien In-HCl and 200 parts of ice poured. The precipitate is filtered off, washed with water and dried DIt.- ITracrystallization of the precipitate from nitro methane gives K- -; p-Met: ö.oxyphenyl) bicyclo ^^ j ^ / octane-i-carbohydroxar / Rä'üx ¹ «τοπ melting point 217 ⁰ C (dec.). With iron (III) chloride in alcohol, the crystals turn deep red.

Analysis: for C ₁₆ I. C.
3ECTB H N Calculated ₉ 79 7 _t 69 5.09 Found: , 48 7.55 5.04 5 I ₂₁ NO _3: 69 69 example 1

A solution of 8.64 parts of 4- (p-methoxyphenyl) bicyclo / 2 \ 2,27octane-1-carboxylic acid ethyl ester and 9 * 6 parts

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99% hydrazine in 30 parts of amyl alcohol is refluxed for 3 hours. The product is evaporated under reduced bridge. The residue is talliaiert from toluene umkri- ■ to give 4 ~ (p ^ lethoxyphenyl) bicyclo / 2 _t 2,27octan-1-earbonsäurahjdrazid -from melting point will hold 196.5 to 198.5 ⁰ C • »·

Example 16

, Hai solution of 0.010 mol of 4 ~ (p-ithoxyphenyl) -bicycΙοί ^^, ^ oct ^ -en-i-oarboneäureäthyleater and 0.010 mol

Methylhydrate in 100 al of alcohol is 16 hours in one ι

ο '

The autoclave is kept at 150 ° C. under the autogenous pressure. That

(Oeaieeh is cooled and evaporated, whereby ff'-Methrl - * -

f (> -ethoxyphenyl) bicyclo ^ 2,2, jg7oot-2-en-1-carbeB * iujfe- {

mydrasid is obtained. !

Un · repetition of the experiment described in Example 16, but using an equivalent amount '* »(P-Hjdrexyph * nyl) -bioyelo / 2,2,27octane-1-« arbene acid-

"Ethyleeter in place of the 4- (p-ethoxyphenyl) bioyclo-) / l?, 2 _t 27oct>2-" n-1 ~ carboneäuraäthylester and one "

Talents amount 1,1-dimethylhydrazine instead of the methylhydrasine used in Example 16 gives If'-methyl-4- (p-ithoxyphenyl) bicyclo / 5,2,27oc t-2-en-1 -carboxylic acid - hydraeid.

Example 17 A mixture of 2.88 parts of N ¹ N ¹ -dimethyl-4- (p-hydroxy-

phenyl) bioyclo / ^, 2,27octan-1-carboneäurehydra * id, 54 parts of acetic anhydride and 4 parts of anhydrous sodium acetate is refluxed for 1 hour. After cooling down 20 parts of water are added dropwise to the mixture. The GE mix is left to stand for 12 hours and then under ver evaporated under reduced pressure. The residue is with a mixture of a 5% sodium bicarbonate solution and Treated with chloroform. The chloroform extract is washed with water and dried with anhydrous sodium sulfate net and evaporated, with N'N'-dimethyl - ^ - Cp-acetoxy-

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BATH

phenyl) bicyclo / 2,2,27octane-1-carboxylic acid hydrazide will.

The compounds according to the invention can be used to prevent pregnancy by the method according to Invention can be administered in any suitable manner. For example, administration can be parenteral, i.e. subcutaneously or intramuscularly. Oral or rectal administration is also possible.

In most! Animals these compounds are effective, if they were in a single dose or in divided doses within a time from 0 to 15 after coitus are given. Preferably, these compounds are administered in a single dose according to the. Coitus, however, before estimated time of implantation of the fertilized egg given 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 of administration with a dose of 0.001 to 50 mg of active ingredient per kg per day given to one or more vagaries, 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 method according to the invention can therefore be added to those previously known Methods of combating rodents or as a substitute for these methods are used.

Example 18

In immature rats (28 days old), precocious puberty is determined with a single dose of the serum from pregnant mice, Gonadotrophin, induced, whereupon the animals with normal

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male rats are mated. A suspension of 4- (p-methoxyphenyl) bicyclo _/ / ?, 2, g / oGtan-l-carboxylic acid hydrazide in sesame oil is administered orally daily for a period of 6 days, starting on the day on which sperm or. a vaginal plug can be found. 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. Control animals have an average of 8 implantation sites. When a series of graduated doses is administered, the dose at which 50% of the animals show no sign of gestation, the EDj- ₀ , is found to be between 0.31 and 1.24 mg / kg / day.

The experiment described in Example 18 is repeated, but using 4- (p-methoxyphenyl) bicyclo- / ?, 2,27octane-1-carbohydroxamic acid instead of the compound used in the experiment described above. An ED ₁ -Q of less than 1.24 mg / kg / day is found.

The experiment described in Example 18 is repeated again, but using 4-phenylbicyclic / 2,2,27-octane-1-carboxamide instead of 3 compounds used in the experiment described above. _{The ED ^ 0} is found to be between 1.25 and 4.99 mg / day / kg.

The compounds according to the invention can also be used with good results for preventing pregnancy in other test animals, e.g. mice, guinea pigs, rabbits, Monkeys and chimpanzees, and are also effective in preventing pregnancy in pets such as

JO cows, sheep, pigs and horses. With small animals it is usually convenient to use the compounds according to the invention contained in a capsule or the putter to be administered orally to the animals. In the case of large animals, on the other hand, it is often more practical to use them to be administered parenterally.

The active ingredients _Q semäJ3 * of the invention can be used in the

services according to the invention in the form of tablets, capsules, powder packs 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. 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 composition, 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 about 0.1 to 75% by weight of a 4-phenylbicyclo /?, 2,27octane or -oct-2-an-1-carboxamide or its derivative according to the invention and 99.9 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 contain about 0.5 to 95%, preferably 1 to 50% by weight of the active ingredient.

The active ingredient content therein is preferably about 0.5 to 250 mg, with about 1 to 50 rag being particularly preferred will.

As already mentioned, pharmaceutical-time carriers are suitable sterile liquids, e.g. water and oils from petroleum

JO and oils of animal, vegetable or synthetic origin, e.g., peanut 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, preferred as liquid carrier, especially for injection solutions. Sterile

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Ί 812889

Contains injection solutions, e.g. in saline solution usually about 0.05 to 29%, preferably about 0.1 to 5% by weight of the active ingredient.

As already mentioned, it can be administered orally in a suitable suspension, in a syrup or in an elixir In these carriers the active ingredient is usually contained in an amount of about 0.01 to 5%, preferably about 0.05 to 1% by weight. The pharmaceutical The carrier in such preparations can be an aqueous carrier, e.g. an aromatic water, a syrup or a pharmaceutical mucilage.

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 is added

& 9Γ The invention is further illustrated by the following examples.

Example 19

A large number of unit capsules are manufactured for oral administration by adding conventional two-part hard gelatin capsules containing 10 mg of powdered 4- (p-aoetoxyphenyl) bicyclo / 2,2,27oct-2-en-1-carboxamide, 125 mg Lactose and 1 mg of finely divided fumed silica be filled.

In addition to or in place of the lactose in the above-mentioned preparation, fillers, e.g. anhydrous lactose, kaolin, precipitated calcium carbonate Mannitol, microcrystalline cellulose or the like, with good Results are used.

If necessary, lubricants such as talc, magnesium stearate, Calcium stearate, corn starch, stearic acid, polyethylene glycol 4000 or so in place of the fumed silica with good results in the example

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WSPECTED

19 described preparation can be used.

Example 20

A large number of unit capsules are manufactured for oral administration by using soft gelatin capsules a solution of 4- (p-Hydroxyphenyl) bicyclo ^ 2,2,27oct-2-en-1-carboxamide be filled in sesame oil.

Example 21

A large number of tablets are prepared by conventional methods so that the dosage unit contains 5 mg of active ingredient, 82.9 mg of anhydrous lactose, 2 mg of magnesium stearate, 10 mg of microcrystalline cellulose and 0.1 mg of pyrogenic silicon dioxide. Slow release tablets can also be made by applying suitable coatings. In the case of other tablet formulations, 1 to ψ / ο of the total weight of the tablets can consist of a lubricant, such as talc, stearic acid and magnesium stearate, instead of the fumed silicon dioxide in the composition described above.

As further binders, which are used in place of the anhydrous lactose in the preparation described above can, starch, ÄthyIcellulose, polyethylene glycol are suitable 4000 and the like

Instead of the microcrystalline cellulose in the formulation described above, other fillers, e.g. Lactose, mannitol or the like can be used.

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

Example 22

A paranteral preparation that can be administered by injection is prepared by stirring 0.5% by weight 4- (p-ethoxyphenyl) bicyclo ^ 2,2,27octane-1-carbon-

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acid amide in sterile mineral oil.

Example 2 $

Suppositories for rectal use can be prepared are obtained by stirring 0.25% by weight of 4- (p-metho: xyphenyl) bicyclo / 2 \ 2, ^ oct-2-en-1-carboxylic acid ester 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 be prepared according to the invention, which have been specifically mentioned above, but without any limitation it is intended. The compounds are used in the specified amounts according to known methods, described in the Martin manual mentioned above.

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Claims (1)

Cologne, December 4th, 1968 AvK / IK Claims 1.) Compounds of the general formula where A is a single or double bond, R _{1 is} H, OH, OCH ,, OC ₃ H ₅ or RCO, where urine R is an alkyl radical of 1 to 12 carbon atoms and JU > ^ ^R 5 R ₂ -NH-NH ₂ , NHOH, N ^, NHNv , in which R, R ₂ , R, - or R can be identical or different and are H, CH-, or ethyl and R ₇ and Rh and R ₁ . and Rg together with the nitrogen can form the pyrrolidino, piperidino or morpholine ring systems. 2.) Compounds according to claim 1, wherein R _{1 is} H, OH, OCH ,, OC ₂ H ₅ and RCO, where R is an alkyl of 1 to 4 carbon atoms and Rp and A are as defined in claim: 1. 3.) 4- (p-hydroxyphenyl) bicyclo / ~ 2.2, 2 / octane-1-carboxamide, 4.) 4- (p-hydroxyphenyl) bicyclo / ~ 2,2,2j7oct-2-en- 1 - carboxamide.
5) 4- (p-methoxyphenyl) bicyclo / ~ 2,2,2j7octane-1- carboxamide. 909827 / 1B17. 6.) 4- (p-methoxyphenyl) bicyclo / ~ 2, 2, 2_J7oct-2-en-carboxamide. 7-) 4- (p-ethoxyphenyl) bicyclo / "2,2,2_J7 _oc tan-1-carboamide. 8.) 4- (p-Ethoxyphenyl) bieyclo / ~ 2, 2, 2j7oct-2-en-1-carboxamld. 9.) 4- (p-acetoxyphenyl) bicyclo / ~ 2,2,2_7bctan-loarboxamide. 10.) 4- (p-acetoxyphenyl) bicyclo / 2.2,2_J7oct-2-ene-carboxamide. 11.) Anticonception agents characterized by a content of a) an effective amount of one or more compounds of claims 1 to 10, and to) a pharmaceutically acceptable diluent or a harmless carrier. 12.) A method for preventing the pregnancy of animals, characterized in that the female animals, an effective amount of one or more compounds of claims 1 to 11 administered. 13.) Process for the preparation of compounds of the general formula where A is a single or a double bond , U R _{1 is} H, OH, OCH _{1, OC 2} H ₅ , OC ₅ H ₇ , OC ₁ → H _9, or RCO where R is an alkyl radical of 1 to 12 carbon 909827/1617 atoms is and <R, JU , NHN ^ is where R ,, R ₂ ,, ^R 4 ^R 6 Rc or Rg are identical or different and H, CH, or C _O H _K or R, and R .. as well as R _c and 2 5 ρ 4 '5 Rg together with the nitrogen the ring systems Pyrrolidino, piperidino or morpholino can form, characterized in that a compound the general formula wherein A and R _{1 are} as defined above and are hydrogen or lower alkyl, with ammonia, a primary amine in which the substituent is methyl or ethyl, or a secondary amine in which the substituents are the same or different and each M * fe are methyl or ethyl. 14.) Process for the preparation of compounds of the general formula where A is a single or double bond, R _{1 is} H, OH, OCg ₅ , OC ₂ H ₅ , PC ₅ H ₇ , OC ₂ ^ H ₉ or R-fc-0-, where R is an alkyl radical from 1 to 12 Carbon atoms is R, and Ru can be identical or different and each can be H, CH, or CpH ₁ - or R, and R ₂ , together with the nitrogen, can form the pyrrolidino, piperidino or morpholino ring systems, characterized in that a compound 50 of the general formula 909827/1617 wherein R ₁ and A are as defined above, are reacted with thiallyl chloride and the resulting reaction mixture is treated with a suitable amine. 15 ·) Process for the preparation of compounds, the general formula NHOH wherein A is a single or double bond and R _{1 is} H, OH, OCH ,, OC ₂ H ₅ , OC ₅ H ₇ , OC 1 Hq or R-C-O- is where R is an alkyl radical of 1 to 12 carbon atoms, characterized in that one is a carboxylic acid of the formula wherein A and R _{1 have} the meaning given above, are reacted with with thianyl chloride and the reaction product is treated with hydroxylamine. l6.) Process for the preparation of compounds of the general formula wherein A is a single or double bond, R ₁ H, OH, OCH ,, OC ₃ H ₅ , OC ₅ H ₇ , OC ₂ ^ H ₉ or R-C-O- i-st, where R is an alkyl radical from 1 to 12 909827/1617 Carbon atoms is Rc and Rg can be identical or different and H, CH ~ or CpH ₁ - or R and Rg together with the nitrogen can form the pyrrolidino, piperidino or morphilno ring systems, characterized in that a carboxylic acid ester of the formula lower alkyl wherein A and R have the meaning given above and the lower alkyl radical is an alkyl radical from 1 to 4 carbon atoms is reacted with a suitable hydrazide. 909827/1617