US3637856A - Trans-1-p-(dialkylaminoalkyl) phenyl-1 2-diphenyl-alk-1-enes and salts thereof - Google Patents

Trans-1-p-(dialkylaminoalkyl) phenyl-1 2-diphenyl-alk-1-enes and salts thereof Download PDF

Info

Publication number
US3637856A
US3637856A US559409A US3637856DA US3637856A US 3637856 A US3637856 A US 3637856A US 559409 A US559409 A US 559409A US 3637856D A US3637856D A US 3637856DA US 3637856 A US3637856 A US 3637856A
Authority
US
United States
Prior art keywords
parts
phenyl
mixture
solution
ene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US559409A
Other languages
English (en)
Inventor
Justus Kenneth Landquist
Dora Nellie Richardson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Imperial Chemical Industries Ltd
Original Assignee
Imperial Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB2943665A external-priority patent/GB1080274A/en
Application filed by Imperial Chemical Industries Ltd filed Critical Imperial Chemical Industries Ltd
Application granted granted Critical
Publication of US3637856A publication Critical patent/US3637856A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • C07D295/02—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S426/00—Food or edible material: processes, compositions, and products
    • Y10S426/807—Poultry or ruminant feed

Definitions

  • R and R are alkyl of 1-2 carbon atoms
  • A is alkylene of up to 4 carbon atoms
  • R and R are selected from the group consisting of phenyl, halophenyl, methyl phenyl and methoxyphenyl
  • R is alkyl of 1-4 carbon atoms, and compounds of the formula:
  • This invention relates to alkene derivatives which have valuable therapeutic properties.
  • trans isomer means the compound of the formula:
  • cis isomer means the compound of the formula:
  • R or R there may be mentioned, for example the methyl or ethyl radical
  • NR R group there may be mentioned, for example, a nitrogen-containing heterocyclic radical of not more than 6 ring atoms, for example the N-piperidino, N-morpholino or N-pyrrolidino radical.
  • a straightor branched-chain alkylene radical containing not more than 10 carbon atoms particularly a straightor branched-chain alkylene radical of not more than 5 carbon atoms, for example the methylene (CH ethylene (-CH CH propylene or, 1,1-dimethylethylene 0H (ma) H, radical.
  • R and R there may be mentioned, for example, the phenyl radical, optionally substituted by one or more radicals selected from alkyl and alkoxy radicals of not more than 6 carbon atoms, for example the methyl, ethyl and methoxy radicals, and halogen atoms, for example chlorine and bromine atoms.
  • R there may be mentioned, for example, an alkyl or aralkyl radical of not more than 12 carbon atoms, particularly an alkyl radical of not more than 4 carbon atoms, or an aralkyl radical of not more than 9 carbon atoms, for example the methyl, ethyl, n-propyl, isopropyl or benzyl radical.
  • alkene derivatives of the invention are, for example, a mixture of the cis and trans isomers of 1-rnethylene,
  • salts of the alkene derivatives of the invention there may be mentioned, for example, acid-addition salts, for example salts with an inorganic acid, for example hydrochloric, sulphuric or phosphoric acid, or salts with an organic acid, for example acetic, tartaric, oxalic or citric acid.
  • acid-addition salts for example salts with an inorganic acid, for example hydrochloric, sulphuric or phosphoric acid
  • salts with an organic acid for example acetic, tartaric, oxalic or citric acid.
  • R R NA group is in the mor p-position relative to the CR (OH).CHR*R group and wherein R R R R, R and A have the meanings stated above, or a salt thereof, whereafter, if a substantially pure cis or a substantially pure trans isomer is required, the mixture of isomers, or of the salts thereof, so formed is separated.
  • the dehydration may be effected by the interaction of the alkanol derivative with an acid catalyst, for example with an inorganic acid, for example hydrochloric, hydrobromic or phosphoric acid, or with formic acid.
  • an acid catalyst for example with an inorganic acid, for example hydrochloric, hydrobromic or phosphoric acid, or with formic acid.
  • the interaction may be carried out in an inert diluent or solvent, for example ethanol, and it may be accelerated or completed by the application of heat.
  • the separation may be carried out by methods known to the art for the separation of mixtures of cis and trans isomers, for example by fractional crystallsation or by chromatography.
  • the fractional crystallisation of the mixed isomers in the free base form may be carried out by the use of an organic solvent, for example petroleum ether.
  • the fractional crystallisation of the mixed isomers in the form of a salt thereof, for example the hydrochloride may be carried out by the use of a relatively polar organic solvent, for example ethanol, isopropanol, ethyl acetate or acetone.
  • alkanol derivatives used as starting materials in the above process may be obtained by the interaction of an organometallic compound of the formula:
  • R R NA group is in the mor p-position relative to the X group, wherein R R and A have the meanings stated above, and wherein X stands for the lithium atom or for a radical of the formula -MgY, wherein Y stands for a halogen atom, for example the chlorine or bromine atom, with a carbonyl compound of the formula R .CO.CHR R wherein R R and R have the meanings stated above.
  • the above interaction involving an organometallic compound may be carried out in an inert diluent or solvent, for example tetrahydrofuran or ether, and it may be accelerated or completed by the application of heat.
  • the organo-metallic compounds may be obtained from the corresponding halogeno compounds by conventional means, and the carbonyl compounds may be obtained by alkylation of the corresponding desoxybenzoin derivatives by conventional means.
  • the alkene derivatives of this invention When tested in laboratory animals, the alkene derivatives of this invention exhibit oestrogenic and anti-oestrogenic activity, and they are also capable of preventing implantation of the fertilised ovum when administered at doses substantially less than those required to produce oestrogenic effects. Consequently, the alkene derivatives of the invention are expected to be useful for the modification of the reproductive endocrine status in man and animals, for example the control of precocious puberty or the management of certain aberrations of the menstrual cycle.
  • the geometric isomers are not equivalent in their biological properties, and the trans isomers are preferred for uses in which an anti-oestrogenic effect is desired.
  • compositions which comprise at least one of the alkene derivatives of the invention and a non-toxic, pharmaceutically-acceptable, inert diluent or carrier therefor.
  • compositions suitable for oral use may be, for example, in the form of tablets, capsules, solutions or suspensions in aqueous media or in non-toxic organic liquid media, dispersible powders suitable for the preparation of liquid suspensions, mixtures with animal foodstuffs, or premixes suitable for addition to animal foodstuffs.
  • the said premixes preferably contain between 1% and 10% by weight of active ingredient, and the said mixtures with animal foodstuffs preferably contain between 0.001% and 0.1% by weight of active ingredient.
  • compositions suitable for parenteral use may be, for example, in the form of sterile solutions or suspensions in aqueous media or in non-toxic organic liquid media, or sterile dispersible powders suitable for the preparation of sterile liquid suspensions.
  • compositions may contain excipients known to the art to be useful in the preparation of such compositions, for example wetting, dispersing, suspending, lubricating, sweetening, flavouring and/or colouring agents.
  • the oral compositions may be in the form of tablets wherein the inert diluent or carrier is, for example, maize starch, lactose or alginic acid. There may also be present one or more wetting agents, for example an alkali metal salt of a sulphonated dialkylnaphthalene, for example the sodium salt of sulphonated diisopropylnaphthalene, and one or more lubricating agents, for example magnesium stearate.
  • the said tablets may contain between 1 mg. and 500 mg, of active ingredient.
  • the oral compositions may be in the form of gelatin capsules containing the active ingredient only or in the form of gelatin capsules containing the active ingredient in admixture with an inert diluent, for example lactose or soribtol.
  • an inert diluent for example lactose or soribtol.
  • the dose in humans is likely to be between 5 mg. and 100 mg. per day.
  • EXAMPLE 1 A solution of 6 parts of l-p-(2-dimcthylaminoethyl) plienyl-l,Z-diphenylbutan-l-ol in 50 parts of ethanol is acidified to pH 2 with concentrated hydrochloric acid. The mixture is heated under reflux for 16 hours, and the solvent is then evaporated under reduced pressure. The residue is dissolved in 50 parts of hot water, and the solution is made strongly alkaline with aqueous sodium hydroxide solution. The mixture is cooled and extracted twice, each time with 50 parts of ether. The combined ethereal extracts are dried, and the dried solution is treated with an excess of ethereal hydrogen chloride solution.
  • a solution of 25 parts of sodium nitrite in 100 parts of water is added slowly to a stirred solution of 112 parts of p-(Z-dimethylaminoethyl)aniline dihydrobromide in a mixture of 100 parts of water and 120 parts of 48% aqueous hydrobromic acid at 5 C., until an excess of nitrous acid can be detected by starch iodide paper.
  • the diazonium solution thus obtained is added to a solution of 35 parts of cuprous bromide in 150 parts of 48% aqueous hydrobromic acid, and the mixture is heated at 90-100 C. for 1 hour. The reaction mixture is allowed to cool, and is then made strongly alkaline with aqueous sodium hydroxide solution.
  • EXAMPLE 2 The process described in Example 1 is repeated except that the Grignard reagent prepared from 22.8 parts of N,N-dimethyl-2(p-bromophenyl)ethylamine, is treated with 12.7 parts of 4-methoxy-a-ethyldesoxybenzoin, and the resulting 1 p (Z-dimethylaminoethyl)-phenyl-l-pmethoxyphenyl-2-phenylbutan-l-ol is obtained as a syrup and used in the final stage Without further purification.
  • EXAMPLE 3 A mixture of 13.4 parts of 1-p-piperidinoethylphenyl- 1,2-diphenylbutan-1-ol, 120 parts of ethanol and parts of 10 N-aqueous hydrochloric acid is heated under reflux for 3 hours. The solution is evaporated to dryness under reduced pressure and the residue is stirred with water. 10 N-aqueous sodium hydroxide solution is added and the mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulphate. The chloroform is evaporated, and the residue is crystallised first from aqueous ethanol, then from methanol and finally from petroleum ether (B.P. 4060 C.).
  • the 1-p-piperidinoethylphenyl-1,2-diphenylbutan-l ol used as starting material may be prepared as follows:
  • N-(p-bromophenylacetyl)piperidine in 700 parts of dry ether is added dropwise over 20 minutes to a stirred suspension of 8.3 parts of lithium aluminium hydride in 1500 parts of dry ether.
  • the mixture is stirred and heated under reflux for 18 hours, and 11 parts of ethyl acetate and 100 parts of Water are then cautiously added.
  • the ethereal phase is separated and extracted three times, each time with 100 parts of 2 N-aqueous hydrochloric acid.
  • the combined acidic extracts are made strongly alkaline with aqueous sodium hydroxide solution and the mixture is extracted with ether.
  • the ethereal extract is dried and evaporated, and there is thus obtained N-2-(p-bromophenyl)ethylpiperidine, which is used without further purification.
  • a solution of 25.6 parts of N-Z-(p-bromophenyl)ethylpiperidine in 50 parts of dry tetrahydrofuran is added dropwise to a stirred suspension of 2.28 parts of magnesium in 50 parts of dry tetrahydrofuran.
  • the mixture is stirred and heated under reflux for two hours, and a solution of 10.6 parts of a-ethyldesoxybenzoin in 50 parts of tetrahydrofuran is then added.
  • the mixture is cooled to 10 C. and decomposed by the addition of a solution of 60 parts of ammonium chloride in 150 parts of water.
  • the organic layer is separated, and the aqueous layer is extracted three times, each time with 100 parts of ether.
  • EXAMPLE 4 A solution of 9 parts of l-p-(Z-dimethylaminoethyl) phenyl-2-phenyl-l-p-tolylbutan-l-ol in a mixture of 400 parts of ethanol and 50 parts of concentrated hydrochloric acid is heated under reflux for 24 hours, and the solvent is then evaporated under reduced pressure. The residue is dissolved in 500 parts of water, and the solution is made alkaline with sodium hydroxide solution. The alkaline solution is extracted three times, each time with 200 parts of ether. The extracts are combined, dried and evaporated.
  • the l-p-(Z-dimethylaminoethyl)phenyl-Z-phenyl 1 ptolylbutan-l-ol, M.P. 128130 C., used as starting material may be obtained by repeating the process described in Example 1 for the preparation of 1-p-(2-dimethylaminoethyl)phenyl-1,2-diphenylbutan-1-ol except that the a-ethyldesoxybenzoin is replaced by a-ethyl-4-methyldesoxybenzoin.
  • EXAMPLE 5 A mixture of 12.8 parts of 1-p-(2 dimethylaminoethyl)phenyl-1,2-di-p-chlorophenylbutan-l-ol, 400 parts of ethanol and 50 parts of concentrated hydrochloric acid is heated under reflux for 24 hours and then evaporated to dryness. The residue is crystallised once from a mixture of 40 parts of ethanol and 50 parts of concentrated hydrochloric acid, and then three times from ethanol. There is thus obtained 1-p-( 2-dimethylaminoethyl)phenyltrans-l,2-di-p-chlorophenylbut-l-ene hydrochloride, M.P. 251-253 C. (base, M.P. l13-l15 C.).
  • the 1-p-(2-dimethylaminoethyl)phenyl 1,2 di-p-chlorophenylbutan-l-ol, M.P. 156158 C., used as starting material may be obtained by repeating the process described in the second part of Example 1, except that that the a-ethyl desoxybenzoin is replaced by 4,4'-dichloroa-ethyldesoxybenzoin, B.P. 150-154 C./0.3 mm., which may be obtained by ethylation of 4,4-dichlorodesoxybenzoin using the procedure described in Example 4.
  • EXAMPLE 6 The process described in Example 5 is repeated except that the l-p-(Z-dimethylaminoethyl)phenyl-1,2-di-pchlorophenylbutan-l-ol is replaced by 1-p-(2-dimethylaminoethyl)phenyl-Z-p-chlorophenyl l p-tolylbutan-l- 01. There is thus obtained 1-p-(Z-dimethylaminoethyl) phenyl-trans-l-p-tolyl 2 p-chlorophenylbut-l-ene hydrochloride, M.P. 259-261 C.
  • the l-p-(2-dimethylaminoethyl)phenyl 2 p-chlorophenyl-l-p-tolylbutan-l-ol, M.P. 135-l37 C., used as starting material may be obtained by repeating the process described in the second part of Example 1 except that the 12.2 parts of a-ethyldesoxybenzoin is replaced by 13.5 parts of 4-chloro-a-ethyl-4-methyldesoxybenzoin.
  • the 4-chloro-u-ethyl 4 methyldesoxybenzoin, B.P. 150-152 C./0.4 mm., and the (it-ethyl 4,4 dimethyldesoxybenzoin, B.P. 140144 C./0.25 mm., are obtained by ethylation of 4'-chloro-4-methyldesoxybenzoin and 4,4- dimethyldesoxybenzoin respectively, by using the procedure described in Example 4.
  • EXAMPLE 7 2.8 parts of N,N-dimethyl-3-(m-bromophenyl)propylamine and 40 parts of dry ether are stirred under nitrogen and 6 parts of a 15% W./v. solution of butyl lithium in hexane are added. The mixture is stirred for minutes, and then a solution of 2.6 parts of a-ethyldesoxybenzoin in parts of ether, is added. The mixture is then heated under reflux for 1 hour, and then cooled. The mixture is then poured into 100 parts of Water, the organic layer is separated, and the aqueous solution is extracted twice, each time with parts of chloroform.
  • the extract and the organic layer are combined, dried over sodium sulphate, and evaporated, and the residual syrup is dissolved in 130 parts of chloroform.
  • the chloroform solution is washed three times, each time with 50 parts of N-hydrochloric acid, then with 50 parts of aqueous sodium carbonate solution, and then dried and evaporated.
  • the residue is dissolved in a mixture of parts of ethanol and 10 parts of concentrated hydrochloric acid, and the solution is heated under reflux for 24 hours and then concentrated. 200 parts of water are added, and the solution is made alkaline with sodium hydroxide solution and is extracted three times with parts of chloroform.
  • the extract is dried and evaporated, and the residual syrup is dissolved in benzene and is purified by chromatography on alumina; non-basic impurities are first eluted with benzene, and the basic product is then eluted with ethanol.
  • the base is converted into an oxalate by treatment with oxalic acid in ether-acetone, and by repeated crystallisation of the oxalate from ethanol there is obtained 1-m-(3-dimethylaminopro yl)phenyl-trans-1,2-diphenylbut-l-ene oxalate, M.P. -172 C.
  • N,N-dimethyl 3 (m-bromophenyl)propylamine used as starting material may be prepared as follows:
  • EXAMPLE 8 A mixture of 6.5 parts of l-p-(3-diethylaminopropyl) phenyl-l,2,-diphenylpropan-1-ol, 100 parts of ethanol and parts of concentrated hydrochloric acid is heated under reflux for 3 hours. The acid solution is evaporated, and the residual oil is triturated with ethyl acetate until it solidifies. The solid is collected and recrystallised from ethyl acetate. There is thus obtained 1-p-(3-diethylaminopropyl) phenyl-trans-1,2-dipheny1prop-l-ene hydrochloride, M.P. 167168 C.
  • N,N-dimethyl-3-(p-bromophenyl)propylamine is obtained as follows:
  • EXAMPLE 9 50 parts of l-p-(2-dimethylaminoethyl)phenyl-trans-2 p-chlorophenyl-l-phenylbut-l-ene hydrochloride, 42 parts of maize starch and 7 parts of alginic acid are intimately mixed and granulated using 10% maize starch paste as the granulating agent. The granules are dried at a temperature not exceeding 50 C., then mixed with 1 part of magnesium stearate and compressed into tablets each weighing 50 mg. There are thus obtained tablets suitable for oral administration for therapeutic purposes.
  • R and R are alkyl of 1-2 carbon atoms
  • A is alkylene of up to 4 carbon atoms
  • R and R are selected from the group consisting of phenyl, halophenyl, methylphenyl and methoxy phenyl
  • R is alkyl of 1-4 carbon atoms and the pharmaceutically-acceptable salts thereof.
  • a compound according to claim 1 which is the trans isomer of l-p-(Z-dimethylaminoethyl)phenyl-1,2-di phenylbut-l-ene.
  • a compound according to claim 1 which is the trans isomer of l-p-(Z-dimethylaminoethyl)-phenyl-1-pmethoxyphenyl-2-phenylbut-l-ene.
  • a compound according to claim 1 which is the trans isomer of 1p-(2-dimethylaminoethyl)phenyl-2- phenyl-l-p-tolylbut-l-ene.
  • a compound according to claim 1 which is the trans isomer of 1-p-(2-dimethylaminoethyl)phenyl-2-p-chlorophenyl-1-phenylbut1-ene.
  • a compound according to claim 1 which is the trans isomer of l-p-(2-dimethylaminoethyl)phenyl-1,2-dip-chlorophenylbut-l-ene.
  • a compound according to claim 1 which is the trans isomer of l-p-(Z-dimethylaminoethyl)phenyl-l-ptolyl-2-p-chlorophenylbut-1-ene.
  • a compound according to claim 1 which is the trans isomer of l-p-(Z-dimethylaminoethyl)phenyl-1,2-dip-tolylbut-1-ene.
  • a compound according to claim 1 which is the trans isomer of 1-p-(3-dimethylaminopropyl)phenyl1,2- di-phenylbut-l-ene.
  • a compound according to claim 1 which is the trans isomer of l-p-(3-diethylaminopropyl)-phenyl-1,2-diphenylbut-l-ene.
  • a compound according to claim 1 which is the trans isomer of 1-p(3-diethylaminopropyl)phenyl-1,2-diphenylprop-l-ene.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US559409A 1965-07-12 1966-06-22 Trans-1-p-(dialkylaminoalkyl) phenyl-1 2-diphenyl-alk-1-enes and salts thereof Expired - Lifetime US3637856A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB2943665A GB1080274A (en) 1965-07-12 1965-07-12 Alkene derivatives
GB2943666 1966-06-07

Publications (1)

Publication Number Publication Date
US3637856A true US3637856A (en) 1972-01-25

Family

ID=26259916

Family Applications (1)

Application Number Title Priority Date Filing Date
US559409A Expired - Lifetime US3637856A (en) 1965-07-12 1966-06-22 Trans-1-p-(dialkylaminoalkyl) phenyl-1 2-diphenyl-alk-1-enes and salts thereof

Country Status (9)

Country Link
US (1) US3637856A (enrdf_load_stackoverflow)
BE (1) BE684022A (enrdf_load_stackoverflow)
BR (1) BR6681175D0 (enrdf_load_stackoverflow)
CH (1) CH532011A (enrdf_load_stackoverflow)
DE (1) DE1568854A1 (enrdf_load_stackoverflow)
DK (1) DK122225B (enrdf_load_stackoverflow)
FR (1) FR1509940A (enrdf_load_stackoverflow)
NL (1) NL6609683A (enrdf_load_stackoverflow)
SE (1) SE348183B (enrdf_load_stackoverflow)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5204337A (en) * 1988-10-31 1993-04-20 Endorecherche Inc. Estrogen nucleus derivatives for use in inhibition of sex steroid activity
US5362720A (en) * 1991-06-28 1994-11-08 Endorecherche, Inc. Methods of treating or preventing breast or endometrial cancer with low dose non-masculinizing androgenic compounds
US5681835A (en) * 1994-04-25 1997-10-28 Glaxo Wellcome Inc. Non-steroidal ligands for the estrogen receptor
US7307102B2 (en) 1997-08-15 2007-12-11 Duke University Method of preventing or treating estrogen-dependent diseases and disorders
US20150018341A1 (en) * 2011-12-30 2015-01-15 Centaurus Biopharma Co., Ltd. Novel arylalkene derivatives and use thereof as selective estrogen receptor modulators

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5204337A (en) * 1988-10-31 1993-04-20 Endorecherche Inc. Estrogen nucleus derivatives for use in inhibition of sex steroid activity
US5631249A (en) * 1988-10-31 1997-05-20 Endorecherche Inc. Estrogen nucleus derivatives for use in the inhibition of sex steroid activity
US5362720A (en) * 1991-06-28 1994-11-08 Endorecherche, Inc. Methods of treating or preventing breast or endometrial cancer with low dose non-masculinizing androgenic compounds
US5681835A (en) * 1994-04-25 1997-10-28 Glaxo Wellcome Inc. Non-steroidal ligands for the estrogen receptor
US7307102B2 (en) 1997-08-15 2007-12-11 Duke University Method of preventing or treating estrogen-dependent diseases and disorders
US20150018341A1 (en) * 2011-12-30 2015-01-15 Centaurus Biopharma Co., Ltd. Novel arylalkene derivatives and use thereof as selective estrogen receptor modulators
US9309211B2 (en) * 2011-12-30 2016-04-12 Centaurus Biopharma Co., Ltd. Arylalkene derivatives and use thereof as selective estrogen receptor modulators

Also Published As

Publication number Publication date
BE684022A (enrdf_load_stackoverflow) 1967-01-12
BR6681175D0 (pt) 1973-12-26
CH532011A (de) 1972-12-31
FR1509940A (fr) 1968-01-19
SE348183B (enrdf_load_stackoverflow) 1972-08-28
DK122225B (da) 1972-02-07
DE1568854A1 (de) 1970-09-10
NL6609683A (enrdf_load_stackoverflow) 1967-01-13

Similar Documents

Publication Publication Date Title
US4230862A (en) Antifertility compounds
US3574211A (en) 1-(amino-monohalo-phenyl)-2-amino-alkanols and salts
US3399201A (en) Aminoalkyl-ethano-anthracenes
US3950393A (en) Aminobenzyl-amides and salts thereof
US3215732A (en) Naphthalene derivatives
EP0047536A2 (en) Substituted propylamines
US3637856A (en) Trans-1-p-(dialkylaminoalkyl) phenyl-1 2-diphenyl-alk-1-enes and salts thereof
US3419604A (en) 2-amino- or -amino-alkylene-spiro [cyclopropane-1,9'-fluorenes] and the salts thereof
CZ181891A3 (en) Hexahydroazepine derivatives
US3493606A (en) Trans-isomers of 1-(loweralkylamino-alkoxy) - phenyl - 1,2 - diphenyl-2-haloethylenes and the salts thereof
US5128470A (en) Aromatic carboxamides
US4113777A (en) 2- OR 4-Hydroxy-3,5-dihalo-benzylamines and salts thereof
US3632653A (en) Ethano-anthracenes
US3341537A (en) 1-tertiaryaminoalkoxyphenyl-1, 2-dimonocarbocyclic aryl-alkanes and their pharmaceutically-acceptable acid-addition salts
IE48934B1 (en) N-phenylindoline derivatives,their production and pharmaceutical compositions containing them
US3281423A (en) 1, 3-ethanopiperazines and process
US3526671A (en) Aminoalkylated oximes of dibenzo(a,d)cyclohepten-5-ones
US3663608A (en) 1-phenyl-3-aminoalkyl-1,2,3,4-tetrahydronaphthalenes and the salts thereof
US4705807A (en) Amine derivatives
US4101671A (en) Aminobenzyl-amines and salts thereof
US3683085A (en) Secondaryamino pyridazines
US4139621A (en) N-(4-substituted-3,5-dichloro-phenyl)-piperazines
FI78682C (fi) Foerfarande foer framstaellning av nya terapeutiskt anvaendbara oximetrar.
US3709947A (en) 6-chloropropylidene-1,1a,6,10b-tetrahydrobenzo(a,e)cyclopropa(c)cycloheptenes
US3678076A (en) Tetrahydrodibenzothiophenes