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US3564060A - Pharmaceutically active derivatives of 4 - phenyl - bicyclo (2,2,2)octane and oct-2-ene-1-carbinols and carboxaldehydes - Google Patents

Pharmaceutically active derivatives of 4 - phenyl - bicyclo (2,2,2)octane and oct-2-ene-1-carbinols and carboxaldehydes Download PDF

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US3564060A
US3564060A US688989A US3564060DA US3564060A US 3564060 A US3564060 A US 3564060A US 688989 A US688989 A US 688989A US 3564060D A US3564060D A US 3564060DA US 3564060 A US3564060 A US 3564060A
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octane
bicyclo
ene
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methanol
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Paul E Aldrich
Edward C Hermann
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/34—Monohydroxylic alcohols containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/41—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrogenolysis or reduction of carboxylic groups or functional derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
    • C07C47/46—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
    • C07C47/47—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/44—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing eight carbon atoms

Definitions

  • This invention relates to a novel class of compounds, the 4-phenylbicyclo[2.2.2]octane and oct-Z-ene-l-carbinols and carboxaldehydes. We have further discovered that this class of compounds can be used as antifertility agents in animals to prevent pregnancy.
  • This activity for the compounds of our invention is all the more startling when these compounds are compared in structure to contraceptive agents presently known to the medical art.
  • antifertility agents known to the medical arts.
  • the agents which are known to be most effective for preventing pregnancy are estrogens and progestins.
  • This new mechanism of action has numerous practical advantages such as ease of use, elimination of protracted periods of administration, elimination of a scheduled regimen of medication, and the avoidance of a continual state of pseudopregnancy, which is responsible for many side effects.
  • our invention relates to 4-phenylbicyclo- [2.2.2]octane and oct-2-ene-1-carbinols and carboxalde hydes and their use as antifertility agents.
  • the compounds of my invention are the 4-phenylbicyclo[2.2.2]octane and oct-2-ene-1-carbinols and carboxaldehydes of the following formula:
  • R1 can be H, OH, '-OCH3, -OC2H5, OC3H7,
  • phenyl as used in the general nomenclature for the compounds of this invention throughout this specification means phenyl group or substituted phenyl group. In those compounds in which the phenyl group attached to the bicyclooctane cage is substituted these substituents are para to the position at which the phenyl is attached to the cage structure. Further, the subsituents include H, OH, OCH OC H and alkyl carboxylic acid esters of the paraphenol.
  • carbinols as used herein to describe the compounds of this invention is employed as a generic term which includes the carbinols, as such, and ester derivatives of these carbinols.
  • the intermediate thus formed is cyclized to a pyrone by treatment with anhydrous hydrogenchloride.
  • the alcohols of this invention are conveniently prepared by refluxing a mixture of the appropriate phenyl bicyclo[2.2.2]octane or oct-2-ene compound, a reducing agent and glyme under a nitrogen atmosphere until reaction is complete. After the mixture is cooled, water is cautiously added to the system to decompose the reducing agent. The water is evaporated and the residue dissolved in a mixture of water and an inert organic solvent. The organic layer is then separated from the mixture, dried and evaporated to give the desired phenylbicyclo[2.2.2] octane, 0r oct-2-ene-1-methano1.
  • phenylbicyclo[2.2.2]octane or oct-2-ene compound is used to represent generically 4-phenyl and substituted 4-phenylbicyclo[2.2.2]octane l-carboxylic acid, 4-phenyl and substituted 4-phenylbicyclo[2.2.2]octane-l-carboxylic acid lower alkyl ester, 4-phenyl and substituted 4-phenylbicyclo[2.2.2]oct-2-enel-carboxylic acid and 4-phenyl and substituted 4-phenylbicyclo[2.2.2]oct-2-ene 1 carboxylic acid lower alkyl ester.
  • a preferred reducing agent to be used in a reaction such as the one described above is lithium aluminum hydride.
  • a preferred solvent for use in the above reaction, glyme is anhydrous ethylene glycol dimethyl ether. If desired, other readily available suitable solvents can be substituted for glyme in the above described reaction.
  • the 4-phenylbicyclo[2.2.2]octane and oct-2-ene-1-carboxaldehydes of this invention can be prepared by dissolving the desired 4-phenylbicyclo[2.2.2]octane or oct-2- ene-l-carboxylic acid and lithium metal in methylamine. Ethyl alcohol is then slowly added to this solution and the liquid is evaporated. The residue is dissolved in a quantity of water sufficient to cause solvation and the resultant solution is acidified and stirred, and the resulting precipitate is collected and dried. This precipitate is then dissolved in chloroform.
  • the filtrate is evapoh m f h 1 t Th 4 h 10 rated and the residue is dissolved in a mixture of benzene 3 lcllc acl c are orm t e e i g' and water.
  • the benzene extract is dried with anhydrous y y g Car cm 6 y e MgSO and is evaporated to give 4-phenylbicyclo[2.2.2] .ecte f 1 6 d t d b f octane-l-methanol, M.P.
  • EXAMPLE 1 EXAMPLES 3-6 The procedure of Example 2 is repeated substituting an A mixture of 240 parts of acetophenone and 432 parts equivalent amount of the indicated starting material for of diethyl ethoxymethylenemalonate is dropped into a the 4-phenylbicyclo[2.2.2]octane-l-carboxylic acid methflask containing a solution of 50.6 parts of sodium metal yl ester of Example 2 to obtain the indicated alcohol.
  • the crude yellow precipitate is added to 692 parts of anhydrous hydrogen fluoride at 60 to 70 C.
  • the mixture is allowed to warm to room temperature and the excess hydrogen fluoride is then evaporated.
  • Dichloromethane and water are added to the residue.
  • the dichloromethane extract is washed with dilute NaHCO solution, dried with anhydrous MgSO and then evaporated.
  • the residue is triturated with ethyl acetate to give the corresponding 3-carboethoxy-6-phenyl-2-pyrone, M.P. 107- 109 C.
  • EXAMPLE 15 A solution of 2.46 g. of 4-(p-hydroxyphenyl)bicyclo- [2.2.2]octane-1-methanol in 50 ml. of pyridine is treated with 0.10 mole of acetic anhydride according to the procedure of Example 7, to give 4-(p-acetoxyphenyl)bicyclo- [2.2.2] octane-l-methanol.
  • EXAMPLE 16 A solution of 2.46 g. of 4-(p-hydroxyphenyl)bicyclo- [2.2.2]octane-l-methanol in 50 ml. of pyridine is treated with 0.10 mole of propionyl chloride according to the procedure of Example 7, to give 4-(p-propionoxyphenyl) bicyclo[2.2.2]octane-1-methanol.
  • EXAMPLE 17 A solution of 3.16 g. of 4-(p-acetoxyphenyl)bicyclo- [2.2.2]octane-l-methanol acetic acid ester and 1.38 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, is washed with water, and is dried to give 4-(p-hydr0xyphenyl)bicyclo[2.2.2] octane-l-methanol acetic acid ester.
  • EXAMPLE 18 To a solution of 12.9 g. of 4-(p-methoxyphenyl)bicyclo- [2.2.2]oct-2-ene-l-carboxylic acid in 300 ml. of methylamine is added 3 g. of lithium metal. When the lithium is dissolved, 100 ml. of alcohol is dropped into the solution. The solution is evaporated. The residue is dissolved in 250 ml. of water, and then acidified with 150 ml. of 6 N HCl. The mixture is stirred for one hour. The precipitate is filtered off, washed with water, and dried. The residue is triturated with chloroform, and the extract is chromatographed on silicic acid with chloroform as the eluant.
  • Example 18 The procedure of Example 18 can be repeated substituting 4 (p-methoxyphenyl)bicyclo[2.2.2]octane-1-can boxylic acid for the 4-(p-methoxyphenyl)bicyclo[2.2.2] oct-2-ene-1-carboxylic acid of Example 18 to give as the product 4- (p-hydroxyphenyl) bicyclo [2.2.2]octane-1-carboxaldehyde.
  • EXAMPLE 19 A solution of 0.010 mole of 4-(p-hydroxyphenyl)bicyclo[2.2.2]octane-l-carboxaldehyde, 0.020 mole of sodium methoxide, and 0.020 mole of dimethyl sulfate in 50 ml. of methanol is refluxed for 16 hours. The solution is cooled and then poured into 400 ml. of 3% aqueous NaOH. The resultant precipitate is filtered off, washed with water, and dried to give 4-(pmethoxyphenyl)bicyclo[2.2.2]octane-l-carboxaldehyde.
  • EXAMPLE 20 A solution of 0.010 mole of 4-(p-hydroxyphenyl)bicyclo[2.2.2]oct-Z-ene-l-carboxaldehyde, 0.020 mole of sodium methoxide, and 0.020 mole of diethyl sulfate in 50 ml. of methanol is refluxed for 16- hours. The solution is cooled and then poured into 400 ml. of 3% aqueous NaOH. The resultant precipitate is filtered off, washed With water and dried to give 4-(p-ethoxyphenyl)bicyclo- [2.2.2]octane-l-carboxaldehyde.
  • the compounds of this invention can be administered to prevent pregnancy according to the method of this invention by any suitable means.
  • administration can be parenterally, that is subcutaneously, intramuscularly or intraperitoneally.
  • administration can be by the oral or rectal route.
  • these compounds are eifective when given in a sing-1e dose prior to estimated time of implantation of the fertilized egg.
  • these compounds can be administered in divided doses for from two to six days after mating with equivalent effectiveness if desired in place of the single dose. Therefore, these compounds can be administered in single or divided doses for from 0 to 15 days after coitus.
  • these compounds be administered after coitus, but before estimated time of implantation of the fertilized egg in the uterus.
  • the dosage administered will be dependent upon age, health and weight of the recipient and also upon the fre- 20 quency of administrations. Generally, from 0.001 to 50 mg./kg./day of active ingredient for one or more days is effective to obtain the desired result.
  • a dosage of from 0.005 to 10 mg./kg./day is preferred with the most preferred dosage being in the range of from 0.01 to 5 mg./kg./day.
  • EXAMPLE 23 Immature rats are induced into precocious puberty with a single dose of pregnant mares serum gonadotropin and then are mated with normal males. A suspension of 4 (p methoxyphenyl)bicyclo[2.2.2]octane 1 methanol acetic acid ester in sesame oil is administered orally daily for six days starting on the day of finding sperm or a vaginal plug.
  • mice are killed and their uteri are examined for implantation sites. If any are found, the animal is considered pregnant. Control animals have a mean of eight implantation sites.
  • the dose at which fifty percent of the animals show no evidence of pregnancy, the ED is calculated to be 0.31 mg./kg./day.
  • Example 23 The test of Example 23 is repeated substituting 4-(pmethoxyphenyl)bicyclo[2.2.2]octane 1 methanol for the compound used in the above test.
  • the ED is found to be within a range of doses of from 0.31-1.24 mg./kg./ day.
  • Example 23 The test of Example 23 is again repeated substituting 4 (p-hydroxyphenyl)bicyclo[2.2.2]oct 2 ene 1- carboxaldehyde for the compound used in the above test.
  • the ED is found to be within a range of doses of from 0.31-1.24 mg./kg./day.
  • Example 7 The procedure of Example 7 is repeated substituting the indicated hydroxy compound for the 4-(p-methoxyphe-nyl)bicyclo [2.2.2]octane-1-methanol and indicated acid anhydride or chloride for the acetic anhydride of Example 7 to obtain the indicated ester.
  • the compounds of this invention can also be employed 7 5 with equally satisfactory results to prevent pregnancy in other laboratory animals such as mice, guinea pigs and rabbits and is also effective in preventing pregnancy in domestic animals such as cows, sheep and horses.
  • other laboratory animals such as mice, guinea pigs and rabbits
  • domestic animals such as cows, sheep and horses.
  • these compounds are administered to large animals, it is often more convenient to administer them parenterally.
  • the active ingredient for this invention can be employed in useful compositions according to the present invention in such dosage forms as tablets, capsules, powder packets, or liquid solutions, suspensions, or elixirs, for oral administration or liquid solutions for parenteral use, and in certain cases, suspensions for parenteral use.
  • the active ingredient will ordinarily always be present in an amount of at least 0.01% by weight based on the total weight of the composition and not more than 90% by weight.
  • composition will contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.
  • the solid carrier i a capsule which can be of the ordinary gelatin type.
  • the capsule will be from about 150% by weight of a 4-phenylbicyclo[2.2.2] octane and oct-2-ene-l-carbinol or carboxaldehyde of this invention and 99-50% of a carrier.
  • the active ingredient is tableted with or without adjuvants.
  • the active ingredient is put into powder packets and employed.
  • These capsules, tablets, and powders will generally constitute from about 0.5% to about 95% and preferably from 1% to 50% by weight of active ingredient.
  • These dosage forms preferably contain from about 0.5 to about 250 milligrams of active ingredient, with from about 1 milligram to about 50 milligrams most preferred.
  • the pharmaceutical carrier can, as previously indicated be a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers, particularly for injectable solutions.
  • Sterile injectable solutions such as saline will ordinarily contain from about 0.05% to 25%, and preferably about 0.1% to 5% by weight of the active ingredient.
  • oral administration can be in a suitable suspension or syrup, in which the active ingredient ordinarily will constitute from about 0.01 to 5% and preferably about 0.02 to 1% by weight.
  • the pharmaceutical carrier in such composition can be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.
  • Suitable pharmaceutical carriers are described in Remington Practice of Pharmacy by E. W. Martin and E. F. Cook, a well-known reference text in this field.
  • EXAMPLE 24 A large number of unit capsules are prepared for oral administration by filling standard two-piece hard gelatin capsules weighing about 25 milligrams each with 50 milligrams of powdered 4-(p-methoxyphenyl)bicyclo [2.2.2]oct-2-ene-1-methanol, 125 milligrams of lactose and 1 milligram of Cab-O-Sil finely divided silica.
  • fillers such as anhydrous lactose, kaolin, precipitated calcium carbonate, mannitol, microcriptalline cellulose or the like can be substituted with satisfactory results.
  • lubricants and gliders such as talc, magnesium stearate, calcium stearate, corn starch, stearic acid polyethylene glycol 4,000 or the like can be substituted for the Cab-O-Sil of the formulation of Example 24 with satisfactory results.
  • EXAMPLE 25 A large number of unit capsules are prepared for oral administration by filling soft gelatin capsules with a solution of 4-(p-hydroxyphenyl)bicyclo[2.2.2]octane-1- methanol dodecanoic acid ester in sesame oil.
  • EXAMPLE 26 A large number of tablets are prepared by conventional procedures so that the dosage unit is 10 milligrams of active ingredient, 5 milligrams of gelatin, 1.5 milligrams of magnesium stearate and milligrams of lactose. Slow release tablets can also be used, by applyi'ig appropriate coatings. In other tablet formulations from 1 to 7% of the total weight of the dosage form can be comprised of a lubricant or glidant such as talc, Cab-O-Sil stearic acid or the like in place of the magnesium stearate of the above formulation.
  • a lubricant or glidant such as talc, Cab-O-Sil stearic acid or the like in place of the magnesium stearate of the above formulation.
  • lactose of the above formulation examples include anhydrous lactose, mannitol, microcriptalline cellulose or the like.
  • a typical disintegrating agent such as methylcellulose, velgem, starch, microcriptalline cellulose or the like.
  • EXAMPLE 27 A parenteral composition suitable for administration by injection is prepared by stirring 0.5% by weight of 4 (p hydroxyphenyl)bicyclo[2.2.2]octane 1 methanol acetic acid ester in sterile mineral oil.
  • Suppositories suitable for rectal administration can be prepared by stirring 0.25% by weight of 4-(p-hydroxyphenyl)bicyclo[2.2.2]octane-l-methanol in melted theobroma oil and molding the mass into two gram suppositories.
  • compositions according to this invention can thus readily be made by substituting other compounds for this invention, and including specifically but not limited to compounds for this invention that have specifically been named hereinbefore.
  • the compounds will be used in the amounts indicated in accordance with procedures well known and described in the Martin, Cook text mentioned above.
  • R is a member selected from the group consisting of hydrogen, HO, CH O, C H O, C3H7O-, and C H O
  • R is a member selected from the group consisting of 9 CHO, and --CH 0R wherein R is selected from the group consisting of hydrogen,
  • a compound of claim 1 which is a member of the group consisting of 4 (p methoxypheny1)bicyclo- [2.2.2]0ctane 1 methanol, 4 (p hydroxyphenyl)- bicy'c1o[2.2.2]0ctane 1 methanol, 4 phenylbicyclo- [2.2.2]octane 1 methanol, 4 (p methoxyphenyD- bicyclo[2.2.2]octane 1 octane 1 methanol acetic acid ester, 4 (p hydroxyphenyDbicyclo[2.2.2] octane- 1 carboxaldehyde and 4 (p methoxyphenyl)bicyclo- [2.2.2] octane 1 carboxaldehyde.
  • a compound of claim 1 which is 4-(p-methoxy pheny1)bicyc1o[2.2.2]octane-l-methanol.

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Abstract

THIS DISCLOSURE TEACHES THAT A NEW CLASS OF COMPOUNDS THE 4-PHENYLBICYCLO(2.2.2)OCTANE AND OCT-2-ENE - 1-CARBINOLS AND CARBOXALDEHYDES ARE PHARMACEUTICALLY USEFUL AS ANTIFERTILITY AGENTS. COMPOUNDS WITHIN THE SCOPE OF THIS INVENTION CAN BE FORMULATED INTO INJECTIBLE, ORAL OR RECTAL DOSAGE FORMS AND WHEN ADMINISTERED BY THE APPROPRIATE ROUTE ARE SURPRISINGLY EFFECTIVE TO PREVENT PREGNANCY IN ANIMALS.

Description

United States Patent 3,564,060 PHARMACEUTICALLY ACTIVE DERIVATIVES 0F 4 PHENYL BICYCLO[2.2.2]OCTANE AND OCT- Z-ENE-l-CARBINOLS AND CARBOXALDEHYDES Paul E. Aldrich, Wilmington, and Edward C. Hermann, Newark, Del., assignors to E. I. du Pont de Nemours and Company, Wilmington, Del., a corporation of Delaware No Drawing. Filed Dec. 8, H67, Ser. No. 688,989 Int. Cl. C07c 39/02, 43/20 US. Cl. 260613 3 Claims ABSTRACT OF THE DISCLOSURE This disclosure teaches that a new class of compounds the 4-phenylbicyclo[2.2.2] octane and oct-2-ene 1 carbinols and carboxaldehydes are pharmaceutically useful as antifertility agents.
Compounds within the scope of this invention can be formulated into injectible, oral or rectal dosage forms and when administered by the appropriate route are surprisingly effective to prevent pregnancy in animals.
BACKGROUND OF THE INVENTION This invention relates to a novel class of compounds, the 4-phenylbicyclo[2.2.2]octane and oct-Z-ene-l-carbinols and carboxaldehydes. We have further discovered that this class of compounds can be used as antifertility agents in animals to prevent pregnancy.
This activity for the compounds of our invention is all the more startling when these compounds are compared in structure to contraceptive agents presently known to the medical art.
There are, at present, antifertility agents known to the medical arts. The agents which are known to be most effective for preventing pregnancy are estrogens and progestins.
Presently, the most widely accepted of these pharma ceutical agents are mixtures of steroidal estrogens and progestins.
We have discovered that 4-phenylbicyclo[2.2.2]octane and oct-2-ene-1-carbinols and carboxaldehydes can be used in an entirely different manner to prevent pregnancy. Whereas the estrogen-progestin mixtures now most widely used must be taken for relatively long periods in anticipation of coitus, the compounds of this invention can be administered after coitus to prevent pregnancy. Although the exact mechanism of action is not well understood, animals indicate that, probably nidation is in some manner prevented.
Therefore, in addition to the striking structural difference of the compounds of this invention over known contraceptive agents, it also appears that the compounds of this invention exhibit a mechanism of action that materially differs from presently employed contraceptive drugs.
This new mechanism of action has numerous practical advantages such as ease of use, elimination of protracted periods of administration, elimination of a scheduled regimen of medication, and the avoidance of a continual state of pseudopregnancy, which is responsible for many side effects.
SUMMARY OF THE INVENTION In summary, our invention relates to 4-phenylbicyclo- [2.2.2]octane and oct-2-ene-1-carbinols and carboxalde hydes and their use as antifertility agents.
More particularly, the compounds of my invention are the 4-phenylbicyclo[2.2.2]octane and oct-2-ene-1-carbinols and carboxaldehydes of the following formula:
where A is a single bond or a double bond; R1 can be H, OH, '-OCH3, -OC2H5, OC3H7,
OC4HQ or Of the above compounds wherein R is those compounds are preferred wherein R is an alkyl of one through four carbons.
DESCRIPTION OF THE INVENTION The prefix phenyl as used in the general nomenclature for the compounds of this invention throughout this specification means phenyl group or substituted phenyl group. In those compounds in which the phenyl group attached to the bicyclooctane cage is substituted these substituents are para to the position at which the phenyl is attached to the cage structure. Further, the subsituents include H, OH, OCH OC H and alkyl carboxylic acid esters of the paraphenol.
It is to be also understood that the term carbinols as used herein to describe the compounds of this invention is employed as a generic term which includes the carbinols, as such, and ester derivatives of these carbinols. The intermediate thus formed is cyclized to a pyrone by treatment with anhydrous hydrogenchloride.
The alcohols of this invention are conveniently prepared by refluxing a mixture of the appropriate phenyl bicyclo[2.2.2]octane or oct-2-ene compound, a reducing agent and glyme under a nitrogen atmosphere until reaction is complete. After the mixture is cooled, water is cautiously added to the system to decompose the reducing agent. The water is evaporated and the residue dissolved in a mixture of water and an inert organic solvent. The organic layer is then separated from the mixture, dried and evaporated to give the desired phenylbicyclo[2.2.2] octane, 0r oct-2-ene-1-methano1.
In the above description, phenylbicyclo[2.2.2]octane or oct-2-ene compound is used to represent generically 4-phenyl and substituted 4-phenylbicyclo[2.2.2]octane l-carboxylic acid, 4-phenyl and substituted 4-phenylbicyclo[2.2.2]octane-l-carboxylic acid lower alkyl ester, 4-phenyl and substituted 4-phenylbicyclo[2.2.2]oct-2-enel-carboxylic acid and 4-phenyl and substituted 4-phenylbicyclo[2.2.2]oct-2-ene 1 carboxylic acid lower alkyl ester.
A preferred reducing agent to be used in a reaction such as the one described above is lithium aluminum hydride.
A preferred solvent for use in the above reaction, glyme, is anhydrous ethylene glycol dimethyl ether. If desired, other readily available suitable solvents can be substituted for glyme in the above described reaction.
The 4-phenylbicyclo[2.2.2]octane and oct-2-ene-1-carboxaldehydes of this invention can be prepared by dissolving the desired 4-phenylbicyclo[2.2.2]octane or oct-2- ene-l-carboxylic acid and lithium metal in methylamine. Ethyl alcohol is then slowly added to this solution and the liquid is evaporated. The residue is dissolved in a quantity of water sufficient to cause solvation and the resultant solution is acidified and stirred, and the resulting precipitate is collected and dried. This precipitate is then dissolved in chloroform. The chloroform extract is chromatographed 4 EXAMPLE 2 A mixture of 0.03 mole of 4-phenylbicyclo[2.2.2]octane-l-carboxylic acid methyl ester, 0.1 mole lithium aluminum hydride, and 150 ml. of anhydrous ethylene glycol dimethyl ether (glyme) is refluxed under a nitrogen atmosphere for 4 hours. The mixture is cooled and water is cautiously added until the gray lithium aluminum hydride is converted to a white product. The precipitate is filtered off and is washed with glyme. The filtrate is evapoh m f h 1 t Th 4 h 10 rated and the residue is dissolved in a mixture of benzene 3 lcllc acl c are orm t e e i g' and water. The benzene extract is dried with anhydrous y y g Car cm 6 y e MgSO and is evaporated to give 4-phenylbicyclo[2.2.2] .ecte f 1 6 d t d b f octane-l-methanol, M.P. 78.5-79.6 c., which can be re- T S mVen.t1On.w1 e etter un ers 00 y re erence crystallized from methylcyclohexane. to the following illustrated examples.
EXAMPLE 1 EXAMPLES 3-6 The procedure of Example 2 is repeated substituting an A mixture of 240 parts of acetophenone and 432 parts equivalent amount of the indicated starting material for of diethyl ethoxymethylenemalonate is dropped into a the 4-phenylbicyclo[2.2.2]octane-l-carboxylic acid methflask containing a solution of 50.6 parts of sodium metal yl ester of Example 2 to obtain the indicated alcohol.
Starting material Alcohol Example:
3 4-(panethoxyphenyl)bicyclo[2.2.2]octane-1- 4-(p-methoxyphenyl)bicyclo[2.2.2]octane-1- earboxylie acid methanol, M.P. l27l28 O. 4 4-(p-methoxyphenyl)bieyclo[2.2.2]octane-L 4-(p-methoxyphenyl)bicyelo[2.2.2]octane-lcarboxylic acid ethyl ester. methanol, M.P. 127l28 C. 5 4-(p-ethoxyphenyl)bicycle[2.2.2]oct-2cuc-l- 4-(p-ethoxyphenyl)bieyclo[2.2.2]0et-2-ene-1- I cin'boxylie acid ethyl ester. methanol. 6 4-(p-hydroxyphenyl)bicyclo[2.2.2]octane-1- 4-(p-hydroxypheny carhoxylic acid 1) bicyclo[2.2.2]octane-lmethanol, M.P. 202-204 C.
in 2000 parts of absolute alcohol under a nitrogen atmosphere. The mixture is refluxed for 2 hours with stirring and is allowed to cool. About 1000 to 1500 parts of alcohol is removed by evaporation at reduced pressure, and suflicient ether is added to form a granular or powdery yellow precipitate. The precipitate is filtered off, washed with ether, and dried.
The crude yellow precipitate is added to 692 parts of anhydrous hydrogen fluoride at 60 to 70 C. The mixture is allowed to warm to room temperature and the excess hydrogen fluoride is then evaporated. Dichloromethane and water are added to the residue. The dichloromethane extract is washed with dilute NaHCO solution, dried with anhydrous MgSO and then evaporated. The residue is triturated with ethyl acetate to give the corresponding 3-carboethoxy-6-phenyl-2-pyrone, M.P. 107- 109 C.
EXAMPLE 7 To a solution of 2.46 g. of 4-(p-rnethoxyphenyl)bicyclo [2.2.2]octane-l-methan0l in ml. of dry pyridine is 40 N HCl. When the ice is melted, the precipitate is filtered off, is washed thoroughly with water, and is dried to give 4-(p-methoxyphenyl)bicyclo[2.2.2]octane l methanol acetate ester. Recrystallization of the ester from alcohol gives crystals, M.P. 105-106 C.
EXAMPLES 8-14 The procedure of Example 7 is repeated using the indicated starting alcohol and acid chloride or acid anhydride to give the indicated product.
Alcohol Acid chloride or anhydride Product Ex ample:
8 4-phenylblcycl0[2.2.2]octane-1- Acetic anhydride 4-phenylbieyclo[2.2.2]octane-1-methanol acetic acid methanol. ester.
9 4-(p-ethoxyphenyl)bicyclo[2.2.2]- Dodecanoyl chloride 4-(p-ethoxyphenyl)bicycle[2.2.2]octane-l-mcthanol octane-l-methanol. dodecanoie acid ester.
10 4-(p-methoxyphenyl)b1cyclo[2.2.21- Succinic anhydride 4-(p-methoxyphenyl)bleyclo[2.2.2]oet-2enc1-mcthoet-Zene-l-methanel anol succinic acid mono-ester.
11 4-(p-methoxyphenyl)b1cyclo[2.2.2]- Adipyl chloride 4-(p-rnethoxyphenyl)bieyclo[2.2.2]0ctane-1-methanol octane-l-methanol. adipic acid mono-ester.
12- 4-(p-hydroxyphenyl)b1cyelo[2.2.2]- Acetic anhydride 4-(p acetoxyphenyl)bicycle[2.2.2]octane-l'methanol octaue-l-methanol. acetic acid ester.
13 do Proplonyl chloride 4-(p-propiouoxyphenyl)bicyclol2.2.2]octa11e-1-rncthanol propionic acid ester. 14 4-(p-hydroxyphenyl)blcyc1o[2.2.2]oct- Isobutyryl chloride 4-(p-isobutyroxyphenyl) bicye]o[2.2.2]oet-2 ene-1- 2-ene-1-methanol.
methanol isobutyric acid ester.
Acylation at the phenolic hydroxyl can be accomplished in the following manner.
EXAMPLE 15 A solution of 2.46 g. of 4-(p-hydroxyphenyl)bicyclo- [2.2.2]octane-1-methanol in 50 ml. of pyridine is treated with 0.10 mole of acetic anhydride according to the procedure of Example 7, to give 4-(p-acetoxyphenyl)bicyclo- [2.2.2] octane-l-methanol.
EXAMPLE 16 A solution of 2.46 g. of 4-(p-hydroxyphenyl)bicyclo- [2.2.2]octane-l-methanol in 50 ml. of pyridine is treated with 0.10 mole of propionyl chloride according to the procedure of Example 7, to give 4-(p-propionoxyphenyl) bicyclo[2.2.2]octane-1-methanol.
EXAMPLE 17 A solution of 3.16 g. of 4-(p-acetoxyphenyl)bicyclo- [2.2.2]octane-l-methanol acetic acid ester and 1.38 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, is washed with water, and is dried to give 4-(p-hydr0xyphenyl)bicyclo[2.2.2] octane-l-methanol acetic acid ester.
EXAMPLE 18 To a solution of 12.9 g. of 4-(p-methoxyphenyl)bicyclo- [2.2.2]oct-2-ene-l-carboxylic acid in 300 ml. of methylamine is added 3 g. of lithium metal. When the lithium is dissolved, 100 ml. of alcohol is dropped into the solution. The solution is evaporated. The residue is dissolved in 250 ml. of water, and then acidified with 150 ml. of 6 N HCl. The mixture is stirred for one hour. The precipitate is filtered off, washed with water, and dried. The residue is triturated with chloroform, and the extract is chromatographed on silicic acid with chloroform as the eluant. A fraction is obtained Whose IR [2.9a (OH), 3.7,u. (aldehyde OH), 5.89 (aldehyde C=)] and N.M.R. [(CDCL 0.12-r (1H, singletaldehyde C-H), 2.92-r (4H, quadruplet J c./s.para-disubstituted benzene), 3.45a- (2H, doublet J-1 c./s.olefinic protons), 4.20-r 1H, singlet-phenolic OH), 8.00-8.53-r (8Haliphatic protons)] spectra show it to be 4-(p-hydroxyphenyl)bicyclo [2.2.2] oct-2-ene-1-carboxaldehyde. Recrystallization from xylene gives crystals, M.P. 154l55 C.
The procedure of Example 18 can be repeated substituting 4 (p-methoxyphenyl)bicyclo[2.2.2]octane-1-can boxylic acid for the 4-(p-methoxyphenyl)bicyclo[2.2.2] oct-2-ene-1-carboxylic acid of Example 18 to give as the product 4- (p-hydroxyphenyl) bicyclo [2.2.2]octane-1-carboxaldehyde.
EXAMPLE 19 A solution of 0.010 mole of 4-(p-hydroxyphenyl)bicyclo[2.2.2]octane-l-carboxaldehyde, 0.020 mole of sodium methoxide, and 0.020 mole of dimethyl sulfate in 50 ml. of methanol is refluxed for 16 hours. The solution is cooled and then poured into 400 ml. of 3% aqueous NaOH. The resultant precipitate is filtered off, washed with water, and dried to give 4-(pmethoxyphenyl)bicyclo[2.2.2]octane-l-carboxaldehyde.
EXAMPLE 20 A solution of 0.010 mole of 4-(p-hydroxyphenyl)bicyclo[2.2.2]oct-Z-ene-l-carboxaldehyde, 0.020 mole of sodium methoxide, and 0.020 mole of diethyl sulfate in 50 ml. of methanol is refluxed for 16- hours. The solution is cooled and then poured into 400 ml. of 3% aqueous NaOH. The resultant precipitate is filtered off, washed With water and dried to give 4-(p-ethoxyphenyl)bicyclo- [2.2.2]octane-l-carboxaldehyde.
The compounds of this invention can be administered to prevent pregnancy according to the method of this invention by any suitable means. For example, administration can be parenterally, that is subcutaneously, intramuscularly or intraperitoneally. Alternatively administration can be by the oral or rectal route.
In most animals these compounds are eifective when given in a sing-1e dose prior to estimated time of implantation of the fertilized egg. Alternatively, these compounds can be administered in divided doses for from two to six days after mating with equivalent effectiveness if desired in place of the single dose. Therefore, these compounds can be administered in single or divided doses for from 0 to 15 days after coitus.
It is preferred that these compounds be administered after coitus, but before estimated time of implantation of the fertilized egg in the uterus.
The dosage administered will be dependent upon age, health and weight of the recipient and also upon the fre- 20 quency of administrations. Generally, from 0.001 to 50 mg./kg./day of active ingredient for one or more days is effective to obtain the desired result.
A dosage of from 0.005 to 10 mg./kg./day is preferred with the most preferred dosage being in the range of from 0.01 to 5 mg./kg./day.
These compounds have shown outstanding inhibition of pregnancy in rats as will be seen from the following example. Therefore, the method of this invention can be used in addition to, or as a replacement for presently known rodent control methods.
EXAMPLE 23 Immature rats are induced into precocious puberty with a single dose of pregnant mares serum gonadotropin and then are mated with normal males. A suspension of 4 (p methoxyphenyl)bicyclo[2.2.2]octane 1 methanol acetic acid ester in sesame oil is administered orally daily for six days starting on the day of finding sperm or a vaginal plug.
' One Week after mating, the animals are killed and their uteri are examined for implantation sites. If any are found, the animal is considered pregnant. Control animals have a mean of eight implantation sites.
The dose at which fifty percent of the animals show no evidence of pregnancy, the ED is calculated to be 0.31 mg./kg./day.
The test of Example 23 is repeated substituting 4-(pmethoxyphenyl)bicyclo[2.2.2]octane 1 methanol for the compound used in the above test. The ED is found to be within a range of doses of from 0.31-1.24 mg./kg./ day.
The test of Example 23 is again repeated substituting 4 (p-hydroxyphenyl)bicyclo[2.2.2]oct 2 ene 1- carboxaldehyde for the compound used in the above test. The ED is found to be within a range of doses of from 0.31-1.24 mg./kg./day.
The method of administering a single dose of a compound of this invention is also demonstrated. The above test procedure is again repeated except that the compound of this invention is administered in a single oral dose Hydroxy compound Acid anhydride or chloride Ester Example:
21 4-(p-hydroxyphenyl)bicyclo[2.2.2]- Acetic anhydride 4-(p-acetoxyphenyl)-bicyclo[2.2.2]octane-1-carboxoctane-l-carboxaldehyde. aldehyde. 22 4-(p-hydroxyphenyl)bicyclo[2.2.2]- Propionyl chloride 4-(p-propionoxyphenyl)-bicyclo[2.2.2]octane-1-carboxoct-Q-ene-l-carboxaldehyde. aldehyde.
EXAMPLES 21 AND 22 The procedure of Example 7 is repeated substituting the indicated hydroxy compound for the 4-(p-methoxyphe-nyl)bicyclo [2.2.2]octane-1-methanol and indicated acid anhydride or chloride for the acetic anhydride of Example 7 to obtain the indicated ester.
to female rats on the third day, approximately fifty-three hours after mating.
When the compound administered in this fashion is 4- (p methoxyphenyl)bicyclo[2.2.2]octane 1 methanol the ED is calculated as 0.90 mg./kg./ day.
The compounds of this invention can also be employed 7 5 with equally satisfactory results to prevent pregnancy in other laboratory animals such as mice, guinea pigs and rabbits and is also effective in preventing pregnancy in domestic animals such as cows, sheep and horses. In small animals, it is usually more convenient to administer the compounds of this invention orally in the form of a tablet or capsule, or incorporated in the feed of the animals. On the other hand, when these compounds are administered to large animals, it is often more convenient to administer them parenterally.
The active ingredient for this invention can be employed in useful compositions according to the present invention in such dosage forms as tablets, capsules, powder packets, or liquid solutions, suspensions, or elixirs, for oral administration or liquid solutions for parenteral use, and in certain cases, suspensions for parenteral use. In such compositions, the active ingredient will ordinarily always be present in an amount of at least 0.01% by weight based on the total weight of the composition and not more than 90% by weight.
Beside the active ingredient of this invention the composition will contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.
In one embodiment of a pharmaceutical compositon of this invention, the solid carrier i a capsule which can be of the ordinary gelatin type. In the capsule will be from about 150% by weight of a 4-phenylbicyclo[2.2.2] octane and oct-2-ene-l-carbinol or carboxaldehyde of this invention and 99-50% of a carrier. In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is put into powder packets and employed. These capsules, tablets, and powders will generally constitute from about 0.5% to about 95% and preferably from 1% to 50% by weight of active ingredient. These dosage forms preferably contain from about 0.5 to about 250 milligrams of active ingredient, with from about 1 milligram to about 50 milligrams most preferred.
The pharmaceutical carrier can, as previously indicated be a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil, and the like. In general, water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers, particularly for injectable solutions. Sterile injectable solutions such as saline will ordinarily contain from about 0.05% to 25%, and preferably about 0.1% to 5% by weight of the active ingredient.
As mentioned above, oral administration can be in a suitable suspension or syrup, in which the active ingredient ordinarily will constitute from about 0.01 to 5% and preferably about 0.02 to 1% by weight. The pharmaceutical carrier in such composition can be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.
Suitable pharmaceutical carriers are described in Remington Practice of Pharmacy by E. W. Martin and E. F. Cook, a well-known reference text in this field.
In addition to the exemplary illustrations above, the following examples further explain one aspect of the present invention.
EXAMPLE 24 A large number of unit capsules are prepared for oral administration by filling standard two-piece hard gelatin capsules weighing about 25 milligrams each with 50 milligrams of powdered 4-(p-methoxyphenyl)bicyclo [2.2.2]oct-2-ene-1-methanol, 125 milligrams of lactose and 1 milligram of Cab-O-Sil finely divided silica.
In addition to, or in place of, the lactose in the above formulation, fillers such as anhydrous lactose, kaolin, precipitated calcium carbonate, mannitol, microcriptalline cellulose or the like can be substituted with satisfactory results.
If desired, lubricants and gliders such as talc, magnesium stearate, calcium stearate, corn starch, stearic acid polyethylene glycol 4,000 or the like can be substituted for the Cab-O-Sil of the formulation of Example 24 with satisfactory results.
EXAMPLE 25 A large number of unit capsules are prepared for oral administration by filling soft gelatin capsules with a solution of 4-(p-hydroxyphenyl)bicyclo[2.2.2]octane-1- methanol dodecanoic acid ester in sesame oil.
EXAMPLE 26 A large number of tablets are prepared by conventional procedures so that the dosage unit is 10 milligrams of active ingredient, 5 milligrams of gelatin, 1.5 milligrams of magnesium stearate and milligrams of lactose. Slow release tablets can also be used, by applyi'ig appropriate coatings. In other tablet formulations from 1 to 7% of the total weight of the dosage form can be comprised of a lubricant or glidant such as talc, Cab-O-Sil stearic acid or the like in place of the magnesium stearate of the above formulation.
Other binders which can be substituted for the gelatin of the above formulation include starch, ethylcellulose polyethylene glycol 4,000 or the like.
Other fillers which can be substituted for the lactose of the above formulation include anhydrous lactose, mannitol, microcriptalline cellulose or the like.
In some formulations, it is also preferred to include a typical disintegrating agent such as methylcellulose, velgem, starch, microcriptalline cellulose or the like.
EXAMPLE 27 A parenteral composition suitable for administration by injection is prepared by stirring 0.5% by weight of 4 (p hydroxyphenyl)bicyclo[2.2.2]octane 1 methanol acetic acid ester in sterile mineral oil.
EXAMPLE 28 Suppositories suitable for rectal administration can be prepared by stirring 0.25% by weight of 4-(p-hydroxyphenyl)bicyclo[2.2.2]octane-l-methanol in melted theobroma oil and molding the mass into two gram suppositories.
A large variety of compositions according to this invention can thus readily be made by substituting other compounds for this invention, and including specifically but not limited to compounds for this invention that have specifically been named hereinbefore. The compounds will be used in the amounts indicated in accordance with procedures well known and described in the Martin, Cook text mentioned above.
Since many different embodiment of the invention can be made without departing from the spirit and scope thereof, it is to be understood that the invention is not limited by the specific illustrations except to the extent defined in the following claims.
We claim:
1. A compound of the formula where A is selected from the group consisting of a single bond and a double bond;
R is a member selected from the group consisting of hydrogen, HO, CH O, C H O, C3H7O-, and C H O R is a member selected from the group consisting of 9 CHO, and --CH 0R wherein R is selected from the group consisting of hydrogen,
0 0 A i-@113, ii-omcm,
hemisuccinyl, hemiglutaryl and hemiadipyl.
2. A compound of claim 1 which is a member of the group consisting of 4 (p methoxypheny1)bicyclo- [2.2.2]0ctane 1 methanol, 4 (p hydroxyphenyl)- bicy'c1o[2.2.2]0ctane 1 methanol, 4 phenylbicyclo- [2.2.2]octane 1 methanol, 4 (p methoxyphenyD- bicyclo[2.2.2]octane 1 octane 1 methanol acetic acid ester, 4 (p hydroxyphenyDbicyclo[2.2.2] octane- 1 carboxaldehyde and 4 (p methoxyphenyl)bicyclo- [2.2.2] octane 1 carboxaldehyde.
3. A compound of claim 1 which is 4-(p-methoxy pheny1)bicyc1o[2.2.2]octane-l-methanol.
References Cited UNITED STATES PATENTS
US688989A 1967-12-08 1967-12-08 Pharmaceutically active derivatives of 4 - phenyl - bicyclo (2,2,2)octane and oct-2-ene-1-carbinols and carboxaldehydes Expired - Lifetime US3564060A (en)

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WO2015077611A1 (en) 2013-11-21 2015-05-28 Marquette University Substituted (4'-hydroxyphenyl)cycloalkane compounds and uses thereof as selective agonists of the estrogen receptor beta isoform
WO2018183800A1 (en) * 2017-03-30 2018-10-04 Marquette University Substituted (4'-hydroxyphenyl)cycloalkane and (4'-hydroxyphenyl)cycloalkene compounds and uses thereof as selective agonists of the estrogen receptor beta isoform for enhanced memory consolidation

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DE19534034A1 (en) * 1995-09-14 1997-03-20 Mann & Hummel Filter Fastener device for components in motor industry
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US6044536A (en) * 1995-12-23 2000-04-04 Richard Bergner Gmbh & Co. Method for making an assembly unit
DE19924502C2 (en) * 1999-05-28 2003-08-07 Elringklinger Ag Screw with sleeve
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WO2015077611A1 (en) 2013-11-21 2015-05-28 Marquette University Substituted (4'-hydroxyphenyl)cycloalkane compounds and uses thereof as selective agonists of the estrogen receptor beta isoform
JP2017504567A (en) * 2013-11-21 2017-02-09 マーケット ユニバーシティー Substituted (4'-hydroxyphenyl) cycloalkane compounds and their use as selective agonists of estrogen receptor beta isoforms
AU2014352830B2 (en) * 2013-11-21 2018-12-13 Concordia University, Inc. Substituted (4'-hydroxyphenyl)cycloalkane compounds and uses thereof as selective agonists of the estrogen receptor beta isoform
US10570077B2 (en) * 2013-11-21 2020-02-25 Marquette University Substituted (4'-hydroxyphenyl)cyclohexane compounds and uses thereof as selective agonists of the estrogen receptor beta isoform
WO2018183800A1 (en) * 2017-03-30 2018-10-04 Marquette University Substituted (4'-hydroxyphenyl)cycloalkane and (4'-hydroxyphenyl)cycloalkene compounds and uses thereof as selective agonists of the estrogen receptor beta isoform for enhanced memory consolidation

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