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US3760007A - Bicyclic benzhydrylidene derivatives - Google Patents

Bicyclic benzhydrylidene derivatives Download PDF

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US3760007A
US3760007A US00045535A US3760007DA US3760007A US 3760007 A US3760007 A US 3760007A US 00045535 A US00045535 A US 00045535A US 3760007D A US3760007D A US 3760007DA US 3760007 A US3760007 A US 3760007A
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M Steinman
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Merck Sharp and Dohme LLC
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Schering Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
    • 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
    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/22—All rings being cycloaliphatic the ring system containing eight carbon atoms, e.g. pentalene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms

Definitions

  • ABSTRACT Disclosed herein are bicyclic benzhydrylidene compounds which are non-steriodal hormonal agents useful, for example, in the inhibition of gestation in mammals.
  • R represents hydrogen or lower alkyl
  • R represents hydrogen, lower alkyl, chloro or fluoro
  • R represents hydrogen, hydroxy, lower alkyl, lower alkoxy, lower acyloxy, 2-dilower-alkylaminoethoxy, 2- piperidinoethoxy, 2-pyrrolidinoethoxy, 2- morpholinoethoxy or tetrahydropyran-2'-yloxy
  • R represents hydrogen, halogen or OR,
  • R represents hydrogen, lower alkyl, lower acyl, 2- diloweralkylaminoethyl, Z-piperidinoethyl, 2- pyrrolidinoethyl, 2-morpholinoethyl or tetrahydropyran-2-yl
  • n is either 0 or 1
  • x is either 3 or 4 and y is an integer from 2 to 8.
  • lower alkyl (including the organic moiety of the lower alkyl group) includes straight or branch-chained radicals such as methyl, ethyl, propyl, iso-propyl, n-butyl, tert.-butyl, n-amyl, iso-amyl, n-hexyl and the like.
  • Methyl is the preferred lower alkyl substituent and methoxy is the preferred lower alkoxy substituent.
  • the lower acyl radicals may be derived from such normally pharmaceutically acceptable acids as monobasic lower alkyl carboxylic acids such as acetic, propionic, butyric, isobutyric, valeric and caproic and polybasic organic and inorganic acids such as succinic, maleic, tartaric, citric, carbonic, sulphuric and phosphoric acid. in those instances wherein the acyl moiety represents a polybasic acid, the remaining free acid groups may be converted to the corresponding salts and alkali metals, alkaline earth metals, ammonia or amines for example.
  • the carbobicyclic moiety which hereinafer may be referred to as Q can be attached to the benzhydrylidene moiety through any of its saturated ring carbon atoms.
  • the following groups are representative of Q (the first numeral designates the specific ring carbon atoms of the saturated ring which is attached to the benzhydrylidene moiety):
  • the compounds of this invention can exist in several stereoisomeric forms.
  • the carbobicyclic moiety may give rise to cis and trans isomers involving the relative positioning of the ring substituent e.g. cisand trans-decahydronaphthalene. It is contemplated that all such isomers are embraced by this invention.
  • THe compounds of this invention can be conveniently prepared by dehydrating a benzhydrol of the formula:
  • the carbinols designated by the structural formula ll wherein R is -OR are preferably prepared by reacting a bicyclic carboxy ester (IV) or an equivalent thereof with two moles of a p-substituted phenyl Grignard reagent (V) as follows:
  • the magnesium complex formed by carrying out Reaction Scheme A in the manner conventional for Grignard reactions is decomposed to form the desired carbinol by adding, for example, water or dilute acids such as dilute hydrochloric acid or an aqueous solution of ammonium chloride.
  • the carbinol can be isolated and purified, such steps are not necessary to enable it to be used in preparing the benzhydrylidene compounds of this invention. It is sufficient to recover the carbinol from the aqueous reaction mixture by extraction with a suitable organic solvent for the carbinol. Suitable solvents for this purpose include higher aliphatic alcohols, ethers, ketones, hydrocarbons and halogenated hydrocarbons, e.g. diethyl ether. The extract is then evaporated and the residue is directly used as the starting material in preparing the benzhydrylidene bicyclic compounds of the invention. If desired, the carbinol may be isolated and purified in conventional manner, for instance by recrystallization.
  • the carbinols represented by structural formulae 11 and 111 can be dehydrated to the corresponding benzhydrylidene compounds of this invention (1) by heating under atmospheric or reduced pressure.
  • the dehydration may be facilitated by the addition of various materials, such as sulphuric acid, phosphoric acid, phosphorous pentoxide in boiling benzene, alkali metal hydrogen sulphates, e.g. sodium and potassium hydrogen sulphate, potassium pyrosulphate, iodine in xylene and the like.
  • the dehydration may also be carried out in aqueous to alcoholic alkali solutions, such as potassium or sodium hydroxide dissolved in water or lower alcohols having one to six carbon atoms or with the corresponding lower potassium or sodium alkoxylates.
  • the desired benzhydrylidene bicyclic compounds of the invention thus formed may be isolated in any conventional manner, such as by distillation at a pressure of 0.001 to 5 mm. of Hg and most preferably at a pressure of from about 0.01 to about 0.2 mm. of Hg.
  • the product may then be further purified by reprecipitation or recrystallization.
  • the carbinols represented by the structural formula 11 can also be prepared by reacting a substituted benzophenone (V11) with a halo-ring-substituted bicyclic compound (VIII) and two moles of a reactive metal as follows: Reaction Scheme B:
  • the resulting complex can be destroyed by conventional procedures as, for example, the addition of ammonium chloride and then water followed by extraction with ether.
  • the ether extract can then be poured in strong acid and the aqueous layer extracted with aqueous sodium chloride.
  • the resulting carbinol can be 2QMgX Magnesium Complex Carblnol II where in R Q and X has the above significance.
  • the magnesium complex is worked up as described above.
  • the carbinols represented by the structural formula 111 may be prepared in analogous manner to that for carbinol 11.
  • the desired bicyclic ketone is reacted with the corresponding diphenyl methyl halide or the diphenyl methane in the presence of bimolar quantities of a reactive metal.
  • These carbinols can be worked up and dehydrated in the same manner described above for carbinol 11.
  • R is methyl or an equivalent blocking group rather than hydroxyl or acyl groups.
  • the methoxy-substituted bcnzhydrylidene bicyclic compounds can be converted into the corresponding hydroxy compounds by hydrolysis employing, for example, potassium hydroxide at elevated temperature or boron trifluoride or aluminum trichloride at ambient temperature.
  • the corresponding acyloxy compounds in turn may be prepared by acylating the parent hydroxy compounds employing in known manner conventional acylating agents, e.g. acetic anhydride.
  • acylated compounds of Formula I as for example: 2-(p,p'-dicaproyloxybenzhydrylidene)- cis-bicyclo-[4.4.0 ]-decane; l-( p-acetoxy-p'- isopropoxybenzhydrylidene)-5-methoxy-indane; and disodium-(p,p' dihydroxybenzhydrylidene)-indane disulfate.
  • bicyclic benzhydrylidene compounds of this invention are valuable as non-steroidal hormonal agents. They tend to reduce the level of blood cholesterol. They exhibit both estrogenic and anti-estrogenic activity and are particularly useful as anti-progestational agents.
  • anti-progestational is not meant to refer to the stage of the reproductive process during which the compounds exert their action. Rather the term anti-progestational as used herein refers to the gross result, i.e. that fetal growth is inhibited.
  • the compounds of this invention are used by administering them in the form of a therapeutically effective quantity to the female mammal at a time between from several days prior to the expected onset of the sexual cycle, i.e. menses or estrus, until about one-tenth of the gestation period of the subject mammalian species has elapsed. After that time, the compounds of this invention are ineffective or are so rendered by the chemical changes in the female body and/or fetus which have occured in the interim.
  • the therapeutically effective quantity of the compounds of this invention may readily be ascertained by standard and well-known techniques in the art.
  • One such laboratory technique is the 12-day Mating Test as described in The Journal of Endocrinology (1965), Vol. 33, page 242.
  • the test compound suspended in 1 ml. of a 1 percent carboxymethylcellulose solution, is given by gavage for 11 days to mature female rats of the same strain and approximate weight. During this period they are housed with fertile males at a ratio of three females to one male. Control animals receive the suspending medium only.
  • the number of pregnancies are determined by counting the number of nidation sites. The dosage is increased or decreased, as necessary, to the minimal leval at which no pregnancies result.
  • This dosage in milligrams per kilogram of body weight per day is referred to as the MPD i.e. the minimum protective dose for 100 percent of the test animals.
  • a therapeutically effective dosage range for inhibiting gestation in mammals is readily determined.
  • a therapeutically effective dosage range for the compounds of this invention is considered to be 0.1 75 mg/kg. of body weight. Dosages in the lower part of this range, i.e. 0.1 to 25 mg/kg., are generally sufficient to inhibit gestation when taken before implantation has occurred. Dosages in the upper part of this range, i.e. 2 to 50 mg/kg., are generally necessary to inhibit gestation after implantation has occurred.
  • a suitable regimen consists of administering a single does of0.l 25 mg/kg. ofa compound of this invention either (a) each of the five days preceding the expected onset of the sexual cycle, i.e. menses or estrus, or (b) each day for 5 to 7 days commencing 10 days after said onset. 1f pregnancy is suspected, a daily dose of 2-50 mg/kg. should be administered once daily until pregnancy is no longer suspected or until one-tenth of the gestation period is considered to have elapsed since the suspected day of preganancy. In each specific instance,
  • compositions of this invention may be administered as such or together with suitable carriers which are pharmaceutically acceptable.
  • a carrier is selected according to the route of administration to be used as well as according to the physical properties of the compounds and standard pharmaceutical practice.
  • compositions of this invention are administered orally, although patenteral administration is also therapeutically effective and within the scope of this invention.
  • EXAMPLE 6 250 Mg. Tablets Mix 250 mg. of p,p'-dihydroxy-benzhydrylidene-2- cis-bicyclo[4.4.0]-decane, 50 mg. of powdered sugar, and mg. of corn starch and granulate with a 10% gelatin solution. Dry the granulation and reduce to uniform granules for tableting. Add 45 mg. of corn starch (as disintegrant) and about 1 percent of magnesium stearate (as lubricant). Compress the tablet to a weight of 450 mg. per tablet on a single punch or rotary machine, using 7/16 inch punch.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Disclosed herein are bicyclic benzhydrylidene compounds which are non-steriodal hormonal agents useful, for example, in the inhibition of gestation in mammals.

Description

260/247.2 R, 260/247.5 R, 260/247.7 R, 260/294 R, 260/294.3 R, 260/294.7 R, 260/326.l6, 260/326.5 R, 260/345.8, 260/345.9, 260/475 R, 260/482 R, 260/483 R, 260/485 R, 260/612 R, 260/613 R, 424/346, 424/341, 424/330, 260/570 R I United States Patent 11 1 1111 3,760,007 Steinman [451 Sept. 18, 1973 BlCYCLlC BENZHYDRYLIDENE [51] int. Cl. C07c 39/12 DERIVATIVES [58] Field of Search 260/570 R, M2, 619, [75] Inventor: Martin Steinman, Livingston, NJ. 260,619 A 619 R 619 D [73] Assignee: Schering Corporation, Bloomfield, 5 R f r Cited NJ UNITED STATES PATENTS Filed: J 11, 1970 3,237,200 2/1966 Barany et al 260/619 A x 3,287,397 11 1966 OlSSOIl et al. 260/619 A x [211 App! 45535 3,406,209 10/1968 Barany et al 260/6l9 A Related US. Application Data {63] Continuation-impart Of Ser. Nos. 873,112, om. 31, Primary Examiner-Bernard Helfin 1969, abandoned, and Ser. No. 714,027, March 18, Attorney-Stephen B. Coan, Raymond A. McDonald 1968, abandoned. and Bruce M. Eisen [52] 0.8. CI 260/619 R, 260/619 A, 260/619 D, [57] ABSTRACT Disclosed herein are bicyclic benzhydrylidene compounds which are non-steriodal hormonal agents useful, for example, in the inhibition of gestation in mammals.
4 Claims, No Drawings BICYCLIC BENZHYDRYLIDENE DERTVATIVES This application is a continuation-in-part of my US. applications Ser. No. 873,112, filed Oct. 31, 1969 and -Ser. No. 714,027, filed Mar. 18, 1968 and both now where R represents hydrogen or lower alkyl; R represents hydrogen, lower alkyl, chloro or fluoro; R represents hydrogen, hydroxy, lower alkyl, lower alkoxy, lower acyloxy, 2-dilower-alkylaminoethoxy, 2- piperidinoethoxy, 2-pyrrolidinoethoxy, 2- morpholinoethoxy or tetrahydropyran-2'-yloxy; R represents hydrogen, halogen or OR,; and R represents hydrogen, lower alkyl, lower acyl, 2- diloweralkylaminoethyl, Z-piperidinoethyl, 2- pyrrolidinoethyl, 2-morpholinoethyl or tetrahydropyran-2-yl; n is either 0 or 1; x is either 3 or 4 and y is an integer from 2 to 8.
The foregoing term lower alkyl (including the organic moiety of the lower alkyl group) includes straight or branch-chained radicals such as methyl, ethyl, propyl, iso-propyl, n-butyl, tert.-butyl, n-amyl, iso-amyl, n-hexyl and the like. Methyl is the preferred lower alkyl substituent and methoxy is the preferred lower alkoxy substituent. The lower acyl radicals may be derived from such normally pharmaceutically acceptable acids as monobasic lower alkyl carboxylic acids such as acetic, propionic, butyric, isobutyric, valeric and caproic and polybasic organic and inorganic acids such as succinic, maleic, tartaric, citric, carbonic, sulphuric and phosphoric acid. in those instances wherein the acyl moiety represents a polybasic acid, the remaining free acid groups may be converted to the corresponding salts and alkali metals, alkaline earth metals, ammonia or amines for example.
The carbobicyclic moiety which hereinafer may be referred to as Q can be attached to the benzhydrylidene moiety through any of its saturated ring carbon atoms. The following groups are representative of Q (the first numeral designates the specific ring carbon atoms of the saturated ring which is attached to the benzhydrylidene moiety):
2 2-cis-bicyclo-[4.4.0l-decane; 3-trans-bicyclo-[4.4.0]- decane; 3-cis-bicyclo-[4.4.0]-decane; 2-cis-bicyclo- [4.3.01-nonane; 3-bicyclo-[4.4.01-nonane; 2-cisbicyclo-[3.3.0]-octane; 2-trans-bicyclo-[4.4.0]-deca- 5(6)-ene; l-tetrahydronapthyl; and l-indanyl.
It is noted that the compounds of this invention can exist in several stereoisomeric forms. In particular, the carbobicyclic moiety may give rise to cis and trans isomers involving the relative positioning of the ring substituent e.g. cisand trans-decahydronaphthalene. It is contemplated that all such isomers are embraced by this invention.
THe compounds of this invention can be conveniently prepared by dehydrating a benzhydrol of the formula:
O-FU ti or a benihydryl carbinol of the formula:
Egg; (LOH (III) wherein R is defined immediately below, the hydrortyl group being attached to the O ring carbon atom which is bonded to the benzhydryl moiety.
The carbinols designated by the structural formula ll wherein R is -OR are preferably prepared by reacting a bicyclic carboxy ester (IV) or an equivalent thereof with two moles of a p-substituted phenyl Grignard reagent (V) as follows:
-ooom 2R5MX Magnesium Complex (iv) (v) i Carblnol II Rio-Ox with magnesium in a suitable form such as magnesium tumings in an ether, such as diethyl ether or tetrahydrofuran. If K, were hydrogen or an acyl group, the desired reactions would still proceed but would unneces sarily waste Grignard reagent through the reaction therewith.
The magnesium complex formed by carrying out Reaction Scheme A in the manner conventional for Grignard reactions is decomposed to form the desired carbinol by adding, for example, water or dilute acids such as dilute hydrochloric acid or an aqueous solution of ammonium chloride.
Although the carbinol can be isolated and purified, such steps are not necessary to enable it to be used in preparing the benzhydrylidene compounds of this invention. It is sufficient to recover the carbinol from the aqueous reaction mixture by extraction with a suitable organic solvent for the carbinol. Suitable solvents for this purpose include higher aliphatic alcohols, ethers, ketones, hydrocarbons and halogenated hydrocarbons, e.g. diethyl ether. The extract is then evaporated and the residue is directly used as the starting material in preparing the benzhydrylidene bicyclic compounds of the invention. If desired, the carbinol may be isolated and purified in conventional manner, for instance by recrystallization.
The carbinols represented by structural formulae 11 and 111 can be dehydrated to the corresponding benzhydrylidene compounds of this invention (1) by heating under atmospheric or reduced pressure. The dehydration may be facilitated by the addition of various materials, such as sulphuric acid, phosphoric acid, phosphorous pentoxide in boiling benzene, alkali metal hydrogen sulphates, e.g. sodium and potassium hydrogen sulphate, potassium pyrosulphate, iodine in xylene and the like. The dehydration may also be carried out in aqueous to alcoholic alkali solutions, such as potassium or sodium hydroxide dissolved in water or lower alcohols having one to six carbon atoms or with the corresponding lower potassium or sodium alkoxylates.
The desired benzhydrylidene bicyclic compounds of the invention thus formed may be isolated in any conventional manner, such as by distillation at a pressure of 0.001 to 5 mm. of Hg and most preferably at a pressure of from about 0.01 to about 0.2 mm. of Hg. The product may then be further purified by reprecipitation or recrystallization.
The carbinols represented by the structural formula 11 can also be prepared by reacting a substituted benzophenone (V11) with a halo-ring-substituted bicyclic compound (VIII) and two moles of a reactive metal as follows: Reaction Scheme B:
(VII) (VIII) l Carbinol II wherein M is a reactive metal such as sodium or lithium (butyl lithium) and R 0 and X have the above meanings. This condensation reaction should be carried out in a solvent suitable for reactive metals such as liquid ammonia or ether.
The resulting complex can be destroyed by conventional procedures as, for example, the addition of ammonium chloride and then water followed by extraction with ether. The ether extract can then be poured in strong acid and the aqueous layer extracted with aqueous sodium chloride. The resulting carbinol can be 2QMgX Magnesium Complex Carblnol II where in R Q and X has the above significance. The magnesium complex is worked up as described above.
The carbinols represented by the structural formula 111 may be prepared in analogous manner to that for carbinol 11. For example, by the method of reaction Scheme B, the desired bicyclic ketone is reacted with the corresponding diphenyl methyl halide or the diphenyl methane in the presence of bimolar quantities of a reactive metal. These carbinols can be worked up and dehydrated in the same manner described above for carbinol 11.
As noted above, the various syntheses are more desirably conducted when R is methyl or an equivalent blocking group rather than hydroxyl or acyl groups. The methoxy-substituted bcnzhydrylidene bicyclic compounds can be converted into the corresponding hydroxy compounds by hydrolysis employing, for example, potassium hydroxide at elevated temperature or boron trifluoride or aluminum trichloride at ambient temperature. The corresponding acyloxy compounds in turn may be prepared by acylating the parent hydroxy compounds employing in known manner conventional acylating agents, e.g. acetic anhydride.
The invention is further illustrated by means of the following examples.
EXAMPLE l Preparation of 2 -(p,p'-dihydroxybenzhydry1idene)- cis-bicyclo-[4.4.01-decane and its diacetate'g. of
Add dropwise with vigorous agitation 1 1.6 g. of methyl cis-bicyclo-[4.4.0l-decane-Z-carboxylate (0.06 mole) dissolved in ml. of dry ether to a Grign ard reagent prepared from 3.8 g. of magnesium (0.16 mole) and 26.2 g. of p-bromoanisole (0.14 mole) in 100 ml. of dry ether. Upon completion of the addition, stir the reaction mixture at room temperature for one hour and then reflux for one and a half hours with stirring and then cool and pour onto lON sulfuric acid and stir the resulting mixture overnight.
Separate the ether layer and extract three time with saturated aqueous sodium chloride, dry and the ether layer over anhydrous sodium sulfate and evaporate to dryness. This material distilled at 220C and 0.3 mm. Hg yields 13 g. of material which sets to a hard glass.
Stir 5.8 g. of this material, 2-(p,pdimethoxybenzhydrylidene)-cis-bicyclo-[4.4.0]- decane (0.016 mole) together with 5.8 g. of potassium hydroxide pellets and 30 ml. of triethylene glycol at 210C for four hours. Cool the mixture, pour onto water, and extract with ether.Acidify the aqueous layer with 5N hydrochloric acid and add ether. Wash the ethereal layer with a saturated aqueous solution of so dium chloride to neutral reaction and then dry it over anhydrous sodium sulfate. Evaporate the solution to dryness, dissolve the material in chloroform, treat with charcoal, and crystallize to yield 4.8 g. or 2-(p,p'- dihydroxybenzhydrylidene)-cis-bicyclo-[4.4.0]- decane, m.p. 54C.
Add 3.0 g. (0.009 mole) of this material to 30 ml. of acetic anhydride and add a drop of concentrated sulfuric acid. Heat the mixture on a steam bath for 30 minutes, cool to room temperature, and pour onto water. Extract with ether two times, combine the ether layers and extract the latter two times with saturated aqueous sodium bicarbonate solution. Dry the ether layer over anhydrous sodium sulfate and evaporate. The material is recrystallized from alcohol to yield 1.1 g. of thediacetate, mp. 111C.
EXAMPLE 2 Preparation of 1-methyl-2-(p,pdihydroxybenzhydrylidene)-trans-bicyclo-[4.4.0]- decane and its diacetate Add dropwise with vigorous agitation 8.4 of methyl l-methyl-trans-bicyclo-[4.4.0l-decane-Z-carboxylate (0.04 mole) dissolved in 100 ml. of tetrahydrofuran to a Grignard reagent solution prepared from 52.5 g. of p- (Z-tetrahydropyranyloxy)-bromobenzene (0.2 mole) and 4.83 g. of magnesium (0.2 mole) in 500 ml. of tetrahydrofuran in the cold. Allow the reaction mixture to stand at room temperature for 16 hours and then treat with a small amount of water. Remove the resulting gel by filtration. Add ether to the filtrate, wash the mixture well with water and pour the ether layer onto lON sulfuric acid and stir overnight. Wash the ethereal layer with a saturated aqueous solution of sodium chloride to neutral reaction and then dry it over anhydrous sodium sultate. Evaporate the solution to dryness and recrystallize to obtain 1-methyl-2-(p,p'- dihydroxybenzhydrylidene)-trans-bicyclo-[4.4.0]- decane.
Add 2.3 g. (0.0066 mole) of this material to 12 ml. of acetic anhydride and add a drop of concentrated sulfuric acid. Heat the mixture on a steam bath for 30 minutes, cool to room temperature, and pour onto water.
Extract with ether two times, combine the ether layers and extract the latter two times with saturated aqueous sodium bicarbonate solution. Dry the ether layer over anhydrous sodium sulfate and evaporate. The resultant diacetate is dissolved in alcohol, treated with charcoal,
and allowed to crystallize.
EXAMPLE 3 Preparation of 3-(p,p'-dihydroxybenzhydrylidene)- cis-bicyclo-[3.3.0l-octane and its diacetate Prepare butyl Lithium at 109C from 10.5 g. of lithium shot (1.5 moles) and 102.8 g. of butyl bromide (0.75 mole) in 500 ml. of dry ether. Add to this reagent asolution of 114 g. of di-p-methoxyphenylmethane in 400 ml. of dry tetrahydrofuran with stirring. After an hour at 10C and 62 g. of cis-bicyclo-[3.3.0]-octan-3-one in 200 ml. of dry tetrahydrofuran and allow to warm to room temperature and stir overnight. Add water to the mixture and extract with chlororform. Dry the organic layer over anhydrous sodium sulfate and evaporate to dryness.
To 20 g. of this carbinol in 200 ml. of dry pyridine, add 5.2 ml. of thionyl chloride while cooling in an ice bath. Then heat under reflux for 2 hours. Cool and add 50 ml. of 50 percent sodium hydroxide and heat under reflux for 3/4 hour pour into ice water and extract with ether. Wash the ether layer with water to remove pyridine; dry and evaporate the ether solution. Recrystallize from alcohol.
Stir the crystallized material, 3.7 g. of 3-(p,p'- dimethoxybenzhydrylidene)-cis-bicyclo-[3.3.01-octane (0.011 mole), together with 4 g. of potassium hydroxide pellets and 16 ml. of triethylene glycol at 210C for four hours. Cool the mixture, pour onto water, and extract with ether. Acidify the aqueous layer with 5N hydrochloric acid and add ether. Wash the ethereal layer with a saturated aqueous solution of sodium chloride to neutral reaction and they dry it over anhydrous sodium sulfate. Evaporate the solution to dryness and recrystallize to obtain 3-(p,p'-dihydroxybenzhydrylidene)-cisbicyclo-[3.3.0]-octane.
Add 2.0 g. (0.0066 mole) of this material to 12 ml. of acetic anhydride and add a drop of concentrated sulfuric acid. Heat the mixture on a steam bath for 30 minutes, cool to room temperature, and pour onto water. Extract with ether two times, combine the ether layers and extract the latter two times with saturated aqueous sodium bicarbonate solution. Dry the ether over anhydrous sodium sulfate and evaporate. The resultant diacetate is dissolved in alcohol, treated with charcoal, and
allowed to crystallize.
EXAMPLE 4 Preparation of 2-(p,p'dihydroxybenzhydrylidene)- trans-bicyclo-l4.4.01-decane and its diacetate Dissolve 2.51 g. of sodium metal (0.11 mole) in liquid ammonia. Add 12.1 g. of di-pmethoxybenzophenone (0.05 mole) in ml. of ether. Stir for 15 minutes and add 8.6 g. of 2-chloro-transbicyclo-[4.4.0]-decane (0.05 mole) in ether; stir a further four hours and allow to stand overnight. Carefully add 5.4 g. of ammonium chloride (0.1 mole) and allow the ammonia to evaporate. Treat the mixture with water and extract with ether. Pour the ether layer onto ION sulfuric acid and stir overnight.
' Separate the ether layer and extract three times with saturated aqueous sodium chloride, dry the other layer 'over anhydrous sodium sulfate and evaporate the dryness. Recrystallize from alcohol.
Stir 7.2 g. of the crystallized material, 2-(p,p dimethoxybenzhydrylidene)-trans-bicyclo-[4.4.0]- decane (0.022 mole), together with 6 g. of potassium hydroxide pellets and 25 ml. of triethylene glycol at 210C for four hours. Cool the mixture, pour onto water, and extract with ether. Acidify the aqueous layer with 5N hydrochloric acid and add ether. Wash the ethereal layer with a saturated aqueous solution of sodium chloride to neutral reaction and then dry it over anhydrous sodium sulfate. Evaporate the solution to dryness and recrystallize from ether-petroleum ether to 7 obtain 2-(p,P'dihydroxybenzhydrylidene)- trans-bicyclo-[4.4.0]-decane, m.p. 184186C.
Add 2 g. (0.0066 mole) of this material to 12 ml. of acetic anhydride and add a drop of concentrated sulfuric acid. Heat the mixture on a steam bath for 30 minutes, cool to room temperature, and pour onto water. Extract with ether two times, combine the ether layers and extract the latter two times with saturated aqueous sodium bicarbonate solution. Dry the ether layer over anhydrous sodium sulfate and evaporate. The resultant diacetate is dissolved in alcohol, treated with charcoal, evaporated to dryness, and crystallized from benzenehexane, m.p. 138140C.
In a manner similar to that of Example 4, other compounds of this invention may be prepared by substituting the corresponding halo-ring-substituted compounds (IX) as for example: 2-Chloro-cis-bicyclo-I4.4.0 ]-decane; 3-Chloro-l-methyl-cis-bicyclo-[4.4.0l-decane; 3-Bromo-7-methyl-trans-bicyclo-[4.4.01-decanc; 2-Chloro-cis-bicyclo-[4.3.01-nonane;
. 3-Chloro-8-methyl-trans-bicyclo-[4.3.0]-nonane;
9-Bromo-cis-bicyclo-[4.3.01-nonane; and 2-Chloro-cis-bicyclo-[ 3 .3 .01-octane.
EXAMPLE 5 Preparation of 1-(p,p'-dihydroxybenzhydrylidene)- 6-methoxy-l ,2,3 ,4-tetrahydronaphthalene To a stirred suspension of 6.64 g. of magnesium turnings (0.273 mole) in 25 ml of dry tetrahydrofuran add 2 g. of p-(a-ethoxyethoxy)-bromobenzene and a crystal of iodine. Heat to initiate reaction, then discontinue heating and add the remainder of the p-(aethoxyethoxy)-bromobenzene (66.9 g.; 0.273 mole total) in 50 ml. of dry tetrahydrofuran dropwise at a rate to maintain reflux. Boil under reflux for one hour, cool, and add 18.7 g. of methyl tetrahydro-l-naphthoate (0.091 mole) dropwise in 50 ml. of dry tetrahydrofuran. Boil under reflux for 18 hours. I
Cool the reaction mixture and add 250 ml. of water. Collect the precipitate on a bed of celite and discard; extract the filtrate with ether, wash the ether layer with water and then saturated sodium chloride solution and dry the ether layer over magnesium sulfate. Filter the solution and evaporate the solvent. Take up the residue in 85 ml. of 95 percent ethanol and 1 ml. of concentrated hydrochloric acid, boil under reflux for 5 minutes,, cool and pour onto water. Extract with ether, wash the ether layer with saturated sodium chloride solution and dry it over magnesium sulfate. Filter and concentrate to obtain crystals of the title compound; 6.] g., m.p. 186-189C, tan needles and recrystallize from ethanol (charcoal) to obtain an analytical sample, m.p. l91-2C.
Dissolve 1.5 g. of l-(6-methoxyl ,2,3 ,4- tetrahydronaphthyl)-p-hydroxyphenyl ketone (0.0053 mole) in 150 ml. of tetrahydrofuran. Add one drop of concentrated hydrochloric acid and 75 ml. of ethyl vinyl ether. Boil under reflux for 3 days. Follow the reaction by thin layer chromatography on silica gel using benzene-hexane-ethylacetate (5:521) as eluent.
Cool the reaction micture, dilute with ether and extract with 2X25 ml. portions of percent sodium hydroxide; wash to neutrality with water, and dry over sodium sulfate. Filter, and evaporate to dryness to yield 6-methoxy-1,2,3 ,4-'
a colorless oil (1.8g) which is used directly in the next step.
Prepare the Grignard reagent with 0.39 g. of magnesium turnings (0.016 mole) and 3.92 g. of p-(aethoxyethoxy) bromobenzene (0.016 mole) and 50 ml. of dry tetrahydrofuran. Add 1.83 g. of l-(6-methoxy- 1,2,3,4-tetrahydronaphthyl)-p-(a-ethoxyethoxy) phenyl ketone (0.0052 mole) in 10 ml. of dry tetrahydrofuran boil under reflux for 18 hours.
Cool to ambient temperature and add 10 ml. of water. Decant the liquid and dilute it with ether. Wash the ether solution with saturated sodium chloride solution and dry over magnesium sulfate. Filter, evaporate to dryness and add 30 m1. of 95 percent ethanol. Add 0.1 ml. of concentrated hydrochloric acid and boil under reflux for 5 minutes. Cool, pour onto water, extract with ether; then dry the ether solution (sodium sulfate) and evaporate to dryness.
Add ethanol and allow the solution to crystallize to yield 1 -(p,p'-dihydroxybenzhydrylidene)-6-methoxy- 1,2,3,4-tetrahydronaphthalene; 0.014 gram, m.p. 202 205C.
EXAMPLE 6 Preparation of l-(p-[N,N-diethylaminolethoxy-p'- hydroxy-benzhydrylidine)-6-(N,N- diethylamino)ethoxy-l ,2,3,4-tetrahydro-naphthalene.
Heat under reflux for 4 hours 28.2 grams of l-(6- methoxyl ,2,3,4-tetrahydronaphthyl)-phydroxyphenyl ketone (0.1 mole) in 200 ml. of acetic acid and 150 ml. of hydrobromic acid (48 percent). Pour the reaction product into 600 ml. ice-water, dry and crystallize from ethanol.
Add 26.8 grams (0.1 mole) of this product, l-(6- hydroxy-l ,2,3 ,4-tetrahydronaphthyl)-p-hydroxyphenyl ketone, dissolved in 100 ml. ethanol to 100 ml. of ethanol containing sodium ethoxide (prepared from 9.2 grams of sodium). After cooling to 5C, add with stirring a solution of 17.2 grams of N-(Za-chloroethyl) diethylamine hydrochloride (0.1 mole) in 100 ml. ethanol. Heat the mixture under reflux with stirring for 12 hours. Evaporate ethanol solution, add water and extract the mixture with ether. Extract the ether layer 3 times with 2N hydrochloric acid. Basify the total acid extract with sodium hydroxide solution nd extract the product with ether. Dry the ether layer and evaporate to yield 1-(6-[N,N-diethylamino]ethoxy-1 ,2,3,4- tetrahydronaphthyl)-p-(N,N-diethylamino)ethoxyphenyl ketone.
Add to a stirred suspension of Mg turnings (2.43 grams: 0.1 mole) in 20 ml. of dry tetrahydrofuran 2 grams of p-bromo-a-ethoxyethoxy benzene and a crystal of iodine. Heat the mixture to initiate the reaction and remove the heating source. Add 22.5 grams of the bromo compound (a total of 0.1 mole) in 50 ml. of dry tetrahydrofuran dropwise to maintain reflux. Reflux for one hour and then add dropwise 23.3 grams of l-(6-[N,N- ethylamino1ethoxy-l ,2,3 ,4-tetrahydronaphthyl)-p- (N,N-diethylamino)ethoxyphenol ketone (0.05 mole) in 50 ml. of dry tetrahydrofuran and stir the mixture under reflux for 18 hours.
Cool the reaction mixture and add 200 ml. of water. After filtering through celite, add ether. Wash the ether layer with water, dry, and evaporate. Take up the residue in ml. of percent ethanol and 1 m1. of concentrated hydrochloric acid, reflux 5 minutes, cool and pour into water. Add 2N hydrochloric acid to make the solution strongly acid and wash with ether. Basify the acid layer, wash with ether, and then neutralize the alkaline layer and extract with ether. Dry the ether layer and evaporate to yield the title compound. Prepare the dihydrochloride salt by dissolving the compound in ether and adding ethereal hydrogen chloride. Collect the precipitate and dry.
EXAMPLE 7 Preparation of l-(p-pyrrolidinylethoxy-p'-hydroxybenzhydrylidene)-6-hydroxy-l ,2,3 ,4-tetrahydronaphthalene.
Dissolve 26.8 grams of l-(-hydroxy-l,2,3,4-tetrahydronaphthyl)-p-hydroxyphenyl ketone (0.1 mole) in 300 ml. tetrahydrofuran. Add one drop of concentrated hydrochloric acid and 36 grams of ethyl vinyl ether. Reflux the mixture for 3 days. Cool the reaction, dilute with ether and extract twice with 25 ml. of 10 percent sodium hydroxide. Wash the ethereal extract with water, dry and evaporate under reduced pressure to yield 1-(6-a-ethoxyethoxy-l ,2,3,4- tetrahydronaphthyl)-p-a-ethoxyethoxy-phenyl ketone.
Add 2 grams of l-[2-(p-bromophenoxy)ethyl1- pyrrolidine and a crystal of iodine to a stirred suspension of 2.43 grams of Mg turnings (0.1 mole) in 20 ml. of dry tetrahydrofuran. Heat the mixture to initiate the reaction and remove the heating source. Add dropwise the remainder of the bromo compound (total of 27 grams, 0.1 mole) in 50 ml. of dry tetrahydrofuran to maintain reflux. After refluxing for one hour, add dropwise 23.3 grams of 1-(6-[N,N-diethylamino]ethoxy- 1,2,3 ,4-tetrahydronaphthyl)-p-(N,N-diethylamino)ethoxyphenyl ketone (0.05 mole) in 50 ml. of dry tetrahydrofuran and stir the mixture under reflux for 18 hours.
Cool the reaction and add 200 ml. of water. After filtering through celite, add ether. Wash the ether layer with water, dry, and evaporate. Take up the residue in 85 ml. of 95 percent ethanol and 1 ml. of concentrated hydrochloric acid, reflux for 5 minutes, cool and pour onto water. Add 2N hydrochloric acid to make the solution strongly acid and wash with ether. Basify the acid layer and wash with ether and then neutralize the alkaline layer and extract with ether. Dry the ether layer and evaporate to yield the title compoundQPrepare the hydrochloride salt by dissolving the compound in ether and adding ethereal hydrogen chloride. Collect the precipitate and dry.
EXAMPLE 8 Preparation of 1-(p-hydroxybenzhydrylidene)-6- methoxy-l ,2,3,4-tetrahydronapthalene.
Prepare the Grignard reagent from 0.39 grams of Mg turnings (0.016 mole), 2.51 grams of p-bromobenzene (0.016 mole) in 50 ml. of dry tetrahydrofuran. Add 1.83 grams of 1-(6-methoxy-1,2,3,4- tetrahydronaphthyl)-p-a-ethoxyethoxyphenyl ketone (0.0053 mole) in 10 ml. of water. Decant the liquid and dilute with ether, wash with saturated sodium chloride and dry. Remove the solvent and add 30 ml. of 95 percent ethanol. Add 0.1 ml. concentrated hydrochloric acid and boil the mixture under reflux for 5 minutes. Cool the mixture, pour onto water, and extract with ether. Dry the ether layer and concentrate to yield the title compound.
EXAMPLE 9 Preparation of l-(p-[N,N-diethylamino]eth0xybenzhydrylidine)-6-(N,N-diethylamino)ethoxyl,2,3,4-tetrahydronaphthalene. v
Add 2 grams of p-bromo-benzene and a crystal of iodine to a stirred suspension of Mg turnings (2.43 grams, 0.1 mole) in 20 ml. of dry tetrahydrofuran. Heat the mixture to initiate the reaction and then remove the heating source. Add dropwise the remainder of the bromo compound (total of 15.7 grams, 0.1 mole) in 50 ml. of dry tetrahydrofuran to maintain reflux. After refluxing for one hour, add dropwise 23.3. grams of l-(6- [N,N-diethylamino]ethoxy-l ,2,3,4- tetrahydronaphthyl)-p-(N,N-diethylamino )ethoxyphenyl ketone (0.05 mole) in 50 ml. of dry tetrahydrofuran and stir the mixture under reflux for 18 hours.
Cool the reaction and add 200 ml. of water. After filtering through celite, add ether. Wash the ether layer with water, dry and evaporate. Take up the residue in ml. of percent ethanol and 1 ml. of concentrated hydrochloric acid, reflux for 5 minutes, cool and pour onto water. Add 2N hydrochloric acid to make the solution strongly acid and wash with ether. Basify the acid layer and wash with ether and then neutralize the alkaline layer and extract with ether. Dry the ether layer and evaporate to yield the title compound. Prepare thedihydrochloride salt by dissolving the compound in ether and adding ethereal hydrogen chloride. Collect and dry the precipitate.
Similarly, by using analogous reactants in the abovedescribed syntheses, the other compounds of this invention may be prepared, as for example:
1-( p-piperidinoethoxy-benzhydrylidene)-3-methyl- 5-fluoro-6-piperidinoethoxy 1,2,3,4-tetrahydronaphthalene;
l-(p-morpholinoethoxy-benzhydrylidene)-4-methyl- 6-methoxy-7-chloro-l ,2,3,4-tetrahydronaphthalene;
4P:1612 511::QESEQ PFHZDXSEXEQWk9:. tetra ydropyan-Z'-yloxy-7-fluoro-1 ,2,3 ,4-tetrahydronaphthalene; and
2-(p-diethylaminoethoxy-p-chloro' benzhydrylidene)-5-chloro-1,2,3,4-tetrahydronaphthalene.
By employing the appropriate acylating agent, one may prepare the acylated compounds of Formula I as for example: 2-(p,p'-dicaproyloxybenzhydrylidene)- cis-bicyclo-[4.4.0 ]-decane; l-( p-acetoxy-p'- isopropoxybenzhydrylidene)-5-methoxy-indane; and disodium-(p,p' dihydroxybenzhydrylidene)-indane disulfate.
The bicyclic benzhydrylidene compounds of this invention are valuable as non-steroidal hormonal agents. They tend to reduce the level of blood cholesterol. They exhibit both estrogenic and anti-estrogenic activity and are particularly useful as anti-progestational agents. As used herein anti-progestational is not meant to refer to the stage of the reproductive process during which the compounds exert their action. Rather the term anti-progestational as used herein refers to the gross result, i.e. that fetal growth is inhibited. Although applicant does not wish his inventive concepts to be limited to his theory of the biological mechanism or actions effected by the compounds of this invention, it appears that they inhibit ovulation, suppress the production of progesterone and/or prevent implantation or nidation.
The compounds of this invention are used by administering them in the form of a therapeutically effective quantity to the female mammal at a time between from several days prior to the expected onset of the sexual cycle, i.e. menses or estrus, until about one-tenth of the gestation period of the subject mammalian species has elapsed. After that time, the compounds of this invention are ineffective or are so rendered by the chemical changes in the female body and/or fetus which have occured in the interim.
The therapeutically effective quantity of the compounds of this invention may readily be ascertained by standard and well-known techniques in the art. One such laboratory technique is the 12-day Mating Test as described in The Journal of Endocrinology (1965), Vol. 33, page 242. Therein the test compound, suspended in 1 ml. of a 1 percent carboxymethylcellulose solution, is given by gavage for 11 days to mature female rats of the same strain and approximate weight. During this period they are housed with fertile males at a ratio of three females to one male. Control animals receive the suspending medium only. On the 12th day the number of pregnancies are determined by counting the number of nidation sites. The dosage is increased or decreased, as necessary, to the minimal leval at which no pregnancies result. This dosage in milligrams per kilogram of body weight per day is referred to as the MPD i.e. the minimum protective dose for 100 percent of the test animals.
Accordingly, from the foregoing test procedures as well as by standard laboratory techniques as well as by comparison with known anti-progestational" agents, the therapeutically effective dosage range for inhibiting gestation in mammals is readily determined. On the foregoing bases, a therapeutically effective dosage range for the compounds of this invention is considered to be 0.1 75 mg/kg. of body weight. Dosages in the lower part of this range, i.e. 0.1 to 25 mg/kg., are generally sufficient to inhibit gestation when taken before implantation has occurred. Dosages in the upper part of this range, i.e. 2 to 50 mg/kg., are generally necessary to inhibit gestation after implantation has occurred.
A suitable regimen consists of administering a single does of0.l 25 mg/kg. ofa compound of this invention either (a) each of the five days preceding the expected onset of the sexual cycle, i.e. menses or estrus, or (b) each day for 5 to 7 days commencing 10 days after said onset. 1f pregnancy is suspected, a daily dose of 2-50 mg/kg. should be administered once daily until pregnancy is no longer suspected or until one-tenth of the gestation period is considered to have elapsed since the suspected day of preganancy. In each specific instance,
however, the attending diagnostician will, of course,
determine the dosage amount and frequency taking into account related health factors of the subject female.
The compounds of this invention may be administered as such or together with suitable carriers which are pharmaceutically acceptable. A carrier is selected according to the route of administration to be used as well as according to the physical properties of the compounds and standard pharmaceutical practice. In a preferred embodiment the compositions of this invention are administered orally, although patenteral administration is also therapeutically effective and within the scope of this invention.
Typical formulations incorporating the anti progestational agents of Formula 1 are described below. These formulations are intended to be merely illustrative and no limitation is implied or intended.
EXAMPLE 6 250 Mg. Tablets Mix 250 mg. of p,p'-dihydroxy-benzhydrylidene-2- cis-bicyclo[4.4.0]-decane, 50 mg. of powdered sugar, and mg. of corn starch and granulate with a 10% gelatin solution. Dry the granulation and reduce to uniform granules for tableting. Add 45 mg. of corn starch (as disintegrant) and about 1 percent of magnesium stearate (as lubricant). Compress the tablet to a weight of 450 mg. per tablet on a single punch or rotary machine, using 7/16 inch punch.
EXAMPLE 7 lnjectable Suspension mixture, mg. per ml.
Sterilize the following ingredients separately: mg. of p,p-diacetoxy-benzhydrylidene-2-cis-bicyclo- [4.4.0]-decane, 0.1 mg. of Tween 80 and q.s. of corn oil to make a final volume of one ml. Mix these ingredients aseptically. Attain particle size by use of micronized material or by use of a ball mill, maintaining aseptic conditions. This suspension may be administered subcutaneously and intramuscularly.
Numerous variations of the above-described compositions and methods within the spirit of this invention will be apparent to one skilled in the art.
1 claim:
1. A bicyclic benzhydrylidene compound of the formula wherein R represents hydrogen or lower alkyl; R represents hydrogen, lower alkyl, chloro or fluoro; R represents hydrogen, halogen or hydroxy; x, y and n are integers selected such that the portion of the molecule having the structure tetrahydronaphthalene.

Claims (3)

  1. 2. A compound of claim 1, said compound being 2-(p,p''-dihydroxybenzhydrylidene)-trans-bicyclo-(4.4.0)-decane.
  2. 3. A compound of claim 1, said compound being 2-(p,p''-dihydroxybenzhydrylidene)-cis-bicyclo-(4.4.0)-decane.
  3. 4. A compound of claim 1, said compound being 1-(p,p''-dihydroxybenzhydrylidene)-6-methoxy-1,2,3,4-tetrahydronaphthalene.
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US4139721A (en) * 1978-05-01 1979-02-13 General Electric Company Process for preparing diphenyl haloethylenes
FR2415617A1 (en) * 1978-01-30 1979-08-24 Squibb & Sons Inc NAPHTHALENONE DERIVATIVES AND ANALOGUES USEFUL AS MEDICINAL PRODUCTS AND THEIR PREPARATION PROCESS
US20090176745A1 (en) * 2007-12-31 2009-07-09 Emory University Triarylmethane analogs and their use in treating cancers
US7560589B2 (en) 2003-07-28 2009-07-14 Smithkline Beecham Corporation Cycloalkylidene compounds as modulators of estrogen receptor
US9220682B2 (en) 2009-04-22 2015-12-29 Emory University Nanocarrier therapy for treating invasive tumors

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US3237200A (en) * 1959-02-25 1966-02-22 Barany Ernst Herbert Carboxylic acid esters
US3287397A (en) * 1960-11-22 1966-11-22 Olsson Knut Gunnar P, p' substituted benzhydrylidine cycloalkanes
US3406209A (en) * 1966-02-08 1968-10-15 Ernst H. Barany 1, 1-bis(p-oh-phenyl)-2, 2-disubstituted ethylenes

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3237200A (en) * 1959-02-25 1966-02-22 Barany Ernst Herbert Carboxylic acid esters
US3287397A (en) * 1960-11-22 1966-11-22 Olsson Knut Gunnar P, p' substituted benzhydrylidine cycloalkanes
US3406209A (en) * 1966-02-08 1968-10-15 Ernst H. Barany 1, 1-bis(p-oh-phenyl)-2, 2-disubstituted ethylenes

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2415617A1 (en) * 1978-01-30 1979-08-24 Squibb & Sons Inc NAPHTHALENONE DERIVATIVES AND ANALOGUES USEFUL AS MEDICINAL PRODUCTS AND THEIR PREPARATION PROCESS
US4139721A (en) * 1978-05-01 1979-02-13 General Electric Company Process for preparing diphenyl haloethylenes
US20090253659A1 (en) * 2003-07-28 2009-10-08 Jing Fang Cycloalkylidene Compounds As Modulators of Estrogen Receptor
US7560589B2 (en) 2003-07-28 2009-07-14 Smithkline Beecham Corporation Cycloalkylidene compounds as modulators of estrogen receptor
US7569601B2 (en) 2003-07-28 2009-08-04 Smithkline Beecham Corporation Cycloalkylidene compounds as modulators of estrogen receptor
US7799828B2 (en) 2003-07-28 2010-09-21 Glaxosmithkline Llc Cycloalkylidene compounds as modulators of estrogen receptor
WO2009088838A3 (en) * 2007-12-31 2009-10-08 Emory University Triarylmethane analogs and their use in treating cancers
US20090176745A1 (en) * 2007-12-31 2009-07-09 Emory University Triarylmethane analogs and their use in treating cancers
US20100160296A1 (en) * 2007-12-31 2010-06-24 Emory University Use of imipramine blue and analogs thereof in treating cancers
US20100189762A1 (en) * 2007-12-31 2010-07-29 Emory University Triarylmethane analogs and their use in treating cancers
US8435979B2 (en) 2007-12-31 2013-05-07 Emory University Use of imipramine blue and analogs thereof in treating cancers
US9358226B2 (en) 2007-12-31 2016-06-07 Emory University Triarylmethane analogs and their use in treating cancers
US10376522B2 (en) 2007-12-31 2019-08-13 Emory University Triarylmethane analogs and their use in treating cancers
US9220682B2 (en) 2009-04-22 2015-12-29 Emory University Nanocarrier therapy for treating invasive tumors
US9872834B2 (en) 2009-04-22 2018-01-23 Emory University Nanocarrier therapy for treating invasive tumors

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