EP0975628A1 - Prophylaxie du carcinome mammaire au moyen de modulateurs selectifs du recepteur des oestrogenes - Google Patents

Prophylaxie du carcinome mammaire au moyen de modulateurs selectifs du recepteur des oestrogenes

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Publication number
EP0975628A1
EP0975628A1 EP98915368A EP98915368A EP0975628A1 EP 0975628 A1 EP0975628 A1 EP 0975628A1 EP 98915368 A EP98915368 A EP 98915368A EP 98915368 A EP98915368 A EP 98915368A EP 0975628 A1 EP0975628 A1 EP 0975628A1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
compound
thiophene
benzo
formula
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.)
Withdrawn
Application number
EP98915368A
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German (de)
English (en)
Other versions
EP0975628A4 (fr
Inventor
Andrew Lawrence Glasebrook
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.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0975628A1 publication Critical patent/EP0975628A1/fr
Publication of EP0975628A4 publication Critical patent/EP0975628A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/64—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates to medical methods of treatment. More particularly, the present invention concerns the use of a class of substituted benzo [J ] thiophene compounds for the prophylaxis or prevention of breast carcinoma in a patient in need of such treatment.
  • DCIS Ductal carcinoma in si tu
  • HRT Hormone Replacement Therapy
  • Estrogen is a growth factor required by most breast carcinoma cells in the early stages of this disease. Also it has been established, but yet not fully understood why, that during the course of 85 this disease the cancer cells lose their sensitivity to the effects of estrogen. Eventually, a majority of carcinoma cells become no longer dependent on estrogen for growth and are no longer responsive to any hormonally based therapy, which included "anti-estrogens", GNRH agonists, progestins, 90 and androgens .
  • a method for the prophylaxis or prevention of breast carcinoma in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound having the structure
  • the invention further relates to a method for preventing breast cancer by administrating to human for a sufficient term an effective dose of a compound of formula I or pharmaceutically acceptable salt or pro-drug thereof, where the human has not been diagnosed with, but is
  • R 1 and R 2 are independently selected from the group consisting of hydroxy and alkoxy of one to four carbon atoms.
  • R 3 and R 4 are independently selected from methyl or 140 ethyl, or R 3 and R 4 , taken together with the nitrogen atom to which they are attached, form a pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino ring.
  • the compounds of the present invention are selective 145 estrogen receptor modulators (SERM's), that is, compounds which produce estrogen agonism in one or more desired target tissues while producing estrogen antagonism and/or minimal (i.e. clinically insignificant) agonism in reproductive tissue such as the breast or uterus.
  • SERM's selective 145 estrogen receptor modulators
  • the current invention concerns the discovery that compounds of formula I above are useful for preventing breast cancer.
  • the methods provided by this invention are 155 practiced by administering to a patient in need thereof a dose of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, that is effective to prevent breast cancer.
  • prevention of includes reducing the likelihood of a patient incurring or developing breast cancer.
  • de novo as used in the current invention, 165 means the lack of transformation or metamorphosis of normal breast cells to cancerous or malignant cells in the first instance. Such a transformation may occur in stages in the same or daughter cells via an evolutionary process or may occur in a single, pivotal event.
  • This de novo process is 170 in contrast to the metastasis, colonization, or spreading of already transformed or malignant cells from the primary tumor site to new locations.
  • This invention also relates to the administration of a compound of formula I to a patient who is at risk of developing de novo breast cancer.
  • a person who is at no particular risk of developing breast cancer is one who may develop de novo breast cancer, has no evidence or suspicion of the potential of the disease above normal risk, and who has never had a diagnosis of having the disease.
  • breast carcinoma 180 to the development of breast carcinoma is a personal history of suffering from the disease, or an earlier occurrence of the disease, even if it is in remission with no evidence of its presence.
  • Another risk factor is family history of the disease .
  • alkyl denotes a monovalent radical derived by removal of one hydrogen atom from methane, ethane, or a straight or branched hydrocarbon and includes such groups as methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, tert-butyl and the like.
  • Alkoxy means an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom and includes such groups as methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy and the like.
  • methoxy is the
  • pro-drug means a compound of the present invention bearing a group which is metabolically cleaved in a human to produce a therapeutically active compound of the present invention.
  • pro-drug means a compound of the present invention bearing a group which is metabolically cleaved in a human to produce a therapeutically active compound of the present invention.
  • 200 drug compounds include those in which either or both of the substituent groups R 1 and R 2 of the structure shown above are hydroxy groups which have been protected by a pharmaceutically acceptable hydroxy protecting group which is metabolically cleaved in the body to yield a
  • Hydroxy protecting groups are described in Chapter 2 of T. W. Greene, et al . , "Protective Groups in Organic Synthesis," Second Edition, John Wiley & Sons, Inc., New York, 1991. Simple ether and ester groups are preferred 210 as pro-drug hydroxy protecting groups.
  • Preferred compounds of the present invention include 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidino- ethoxy) phenoxy] benzo [b] thiophene or a pharmaceutically acceptable salt or pro-drug thereof; and 215 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidino- ethoxy) phenoxy] benzo [£>] thiophene or a pharmaceutically acceptable salt or pro-drug thereof.
  • R 5 and R 6 are independently -H or a hydroxy
  • R 5 and R 6 hydroxy protecting groups are moieties which are intentionally introduced during a portion of the synthetic process to protect a group which otherwise might react in the course of chemical manipulations, and is then
  • hydroxy protecting groups include, for example, -C 1 -C4 alkyl, -C 1 -C 4 alkoxy, -CO- (Ci-C ⁇ alkyl), - SO 2 - (C 4 -C 6 alkyl), and -CO-Ar in which Ar is benzyl or
  • substituted phenyl refers to a phenyl group having one or more substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, nitro, halo, and tri (chloro or fluoro) methyl.
  • halo refers to bromo, chloro,
  • R 5 and R 6 substituents are methyl, isopropyl, benzyl, and methoxymethyl.
  • R 5 and R 6 each are methyl are prepared via the procedure described in the above-
  • R 5 can be isopropyl or benzyl and R 6 methyl.
  • the isopropyl or benzyl moiety is selectively removed via standard procedures, and the R 6 methyl protecting group is left as
  • the first steps of the present process for preparing certain compounds of the present invention include selectively placing a leaving group, R 7 at the 3 position of a compound of formula 1_, to
  • 275 form a compound of formula 2_, coupling the product of that reaction with a 4- (protected-hydroxy) phenol, 3_, to form a compound of formula , and selectively removing the R 8 hydroxy protecting group to form a compound of formula £>.
  • the 280 hydroxy protecting groups R 5 , R 6 and R 8 are chosen in such a manner that, in the final step, the hydroxy protecting group R 8 can be selectively removed in the presence of hydroxy protecting groups R 5 and R 6 .
  • R 7 leaving groups include the sulfonates such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate, 4-methoxybenzene- 295 sulfonate, 4-nitrobenzenesulfonate, 2- chlorobenzenesulfonate, triflate, and the like, halogens such as bromo, chloro, and iodo, and other related leaving groups. However, to insure proper placement of the leaving group, the named halogens are preferred, and bromo is
  • reaction is typically run at a temperature from about 40°C to about 80°C.
  • R 8 protecting groups include methoxymethyl, when R 5 and/or R 6 are not methoxymethyl, and benzyl. Of these, benzyl is especially preferred.
  • 320 reactants are commercially available or can be prepared via standard procedures.
  • solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the reaction.
  • organic bases particularly a hindered base such as, for example, 2,4,6- 340 collidine, are preferred solvents.
  • the temperature employed in this step is generally sufficient to effect completion of this coupling reaction, and will influence the amount of time required therefore.
  • the time-to-completion is usually from about 20 to about 60 hours.
  • formula 5_ compounds are prepared by selectively removing the R 8 350 hydroxy protecting group of a formula 4_ compound via well known reduction procedures. It is imperative that the selected procedure will not affect the R 5 and, when present, R 6 hydroxy protecting groups.
  • R 8 is the preferred benzyl moiety, and R 5 and, 355 when present, R 6 each are methyl
  • the present process step is carried out via standard hydrogenolysis procedures.
  • the formula 4_ substrate is added to a suitable solvent or mixture of solvents, followed by the addition of a proton donor to accelerate the reaction and an appropriate 360 hydrogenation catalyst.
  • Appropriate catalysts include noble metals and oxides such as palladium, platinum, and rhodium oxide on a support such as carbon or calcium carbonate. Of these, palladium- on-carbon, particularly 10% palladium-on-carbon, is 365 preferred. Solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the reaction. Typically, ethylacetate and C 1 -C 4 aliphatic alcohols, particularly ethanol, is preferred. For the present reaction, hydrochloric acid serves as an adequate 370 and preferred proton donor.
  • R 4 and R 5 are as defined above, and Q is a bromo or, preferably, chloro, to form a compound of formula 1_.
  • the 385 formula 1_ compound is then deprotected to form a compound of formula I.
  • At least about 1 equivalent of a formula £5 substrate is reacted with 2 equivalents of a formula 6_ 400 compound in the presence of at least about 4 equivalents of an alkali metal carbonate, preferably cesium carbonate, and an appropriate solvent.
  • an alkali metal carbonate preferably cesium carbonate
  • Suitable solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the
  • N,N-dimethylformamide, especially the anhydrous form thereof, is preferred.
  • the temperature employed in this step should be sufficient to effect completion of this alkylation reaction. Typically, ambient temperature is sufficient and preferred.
  • the present reaction preferably
  • this reaction will run to completion in about 16 to about 20 hours.
  • the progress of the reaction can be monitored via standard chromatographic techniques .
  • Q and Q' are the same or different leaving groups.
  • Appropriate leaving groups are those mentioned above.
  • a preferred alkali solution for this alkylation 430 reaction contains potassium carbonate in an inert solvent such as, for example, methyethyl ketone (MEK) or DMF.
  • MEK methyethyl ketone
  • DMF dimethyl methyethyl ketone
  • the unprotected hydroxy group of the formula 5_ compound is converted to a phenoxide ion which displaces one of the leaving groups of the alkylating agent.
  • This reaction proceeds best when the alkali solution containing the reactants and reagents is brought to reflux and allowed to run to completion.
  • reaction times range from about 6 hours to about 20 hours.
  • a compound of formula £ is then reacted with a compound of formula H) selected from 1-piperidine, 1-pyrrolidine, methyl-1- pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, diisopropylamine, or 1-
  • the hydrochloride salt of a compound of formula 3 ⁇ 0 is employed, with piperidine hydrochloride being particularly preferred.
  • the reaction is typically carried out with the alkylated compound of formula
  • Certain preferred compounds of formula I are obtained by cleaving the R 5 and, when present, R 6 hydroxy protecting
  • Reaction Scheme IV An alternative, and preferred, method for the preparation of compounds of the present invention is shown in Reaction Scheme IV.
  • the sulfur atom of a formula 2_ compound is oxidized to form a 475 sulfoxide, 3 ⁇ , which is then reacted with a nucleophilic group to introduce the oxygen atom linker of formula !_ compounds.
  • the sulfoxide moiety of formula 12 compounds is then reduced to provide certain compounds of the present invention.
  • a compound of formula 2_ is selectively oxidized to the sulfoxide, ,12_.
  • a number of known methods are available for the process step [see, e.g., Madesclaire, M., Tetrahedron, 42 (20); 5459-5495 (1986); Trost, B.M., et al., Tetrahedron Letters, 22 (14);
  • reaction 500 peroxide in a mixture of about 20% to about 50% trifluoroacetic acid in methylene chloride.
  • the reaction is run at a temperature from about 10° C to about 50° C, and usually required from about 1 to about 2 hours to run to completion.
  • nucleophilic derivative of formula 13_ is prepared via standard methods.
  • the acidic proton of the nucleophilic group is removed by treatment with a base,
  • a slight excess of sodium hydride or potassium tertbutoxide in a polar aprotic solvent, preferably DMF or tetrahydrofuran.
  • a polar aprotic solvent preferably DMF or tetrahydrofuran.
  • bases include potassium carbonate and cesium carbonate.
  • other solvents such as dioxane or dimethylsulfoxide can be
  • the deprotonation is usually run at a temperature between about 0° C and about 30° C, and usually requires about 30 minutes for completion.
  • a compound of formula XIV is then added to the solution of the nucleophile.
  • the displacement reaction is run at a temperature between 0° C
  • Pro-drug ester compounds of formula I_ are prepared by 530 replacing the 6- and/or 4' -position hydroxy moieties, when present, with a moiety of the formula -OCO(C ⁇ -C ⁇ alkyl), or -OSO 2 (C 2 -C 6 alkyl) via well known procedures. See, e.g., U.S. Pat. No. 4,358,593.
  • a mono- or dihydroxy compound of formula I_ is reacted with an agent such as acyl chloride, bromide, cyanide, or azide, or with an appropriate anhydride or mixed anhydride.
  • an agent such as acyl chloride, bromide, cyanide, or azide, or with an appropriate anhydride or mixed anhydride.
  • the reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or
  • 540 isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, ethylpiperidine, and the like.
  • the reaction also may be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile,
  • acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, e.g., Haslam, e_t
  • Acylation of a 6-position and/or 4' -position hydroxy group also may be performed by acid-catalyzed reactions of the appropriate carboxylic acids in inert organic solvents.
  • Acid catalysts such as sulfuric acid, polyphosphoric acid,
  • ester pro-drug compounds also may be provided by forming an active ester of the appropriate acid, such as the esters formed by such known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, 565 pentachlorophenol, N-hydroxysuccinimide, and 1- hydroxybenzotriazole. See, e.g., Bull. Chem. Soc. Japan, 38 . -1979 (1965), and Chem. Ber., 788 and 2024 (1970).
  • an active ester of the appropriate acid such as the esters formed by such known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, 565 pentachlorophenol, N-hydroxysuccinimide, and 1- hydroxybenzotriazole. See, e.g., Bull. Chem. Soc. Japan, 38 . -1979 (1965), and Chem. Ber., 788 and 2024 (1970
  • a ' -position hydroxy group of a formula I compound is converted to a group of the formula -OSO 2 (C 2 -C 6 alkyl), the mono- or dihydroxy compound is reacted with, for example, a sulfonic anhydride or a derivative of the appropriate sulfonic acid such as a sulfonyl chloride, bromide, or
  • Suitable pharmaceutically acceptable salts include salts formed by typical inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric,
  • organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids.
  • organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids.
  • 610 pharmaceutically acceptable organic acid addition salts include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o- acetoxybenzoate, naphthalene-2-benzoate, bromide,
  • 615 isobutyrate, phenylbutyrate, b-hydroxybutyrate, butyne-1,4- dioate, hexyne-1, 4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, alonate, mandelate, mesylate, nicotinate,
  • 620 isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite,
  • 630 are the hydrochloride and oxalate salts.
  • the pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or slight molar excess of acid.
  • the reactants are generally combined in a mutual solvent such as diethyl ether
  • the salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means. 640
  • the pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.
  • the compounds of this invention are administered by a variety of routes including oral, rectal, transdermal, subucutaneus, intravenous, intramuscular, and intranasal.
  • Another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of Formula I, or a
  • composition 655 pharmaceutically acceptable salt thereof, optionally containing an effective amount of estrogen or progestin, and a pharmaceutically acceptable carrier, diluent, or excipient .
  • 660 comprises from 0.1% to 99.9% by weight of the formulation.
  • pharmaceutically acceptable it is meant the carrier, diluent, excipients and salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • compositions of the present invention are prepared by procedures known in the art using well known and readily available ingredients.
  • the compounds of Formula I either alone, or in combination with an estrogen or progestin compound, are formulated with
  • 670 common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, solutions, injectables, aerosols, powders, and the like.
  • the total active ingredients in such formulations comprises from 0.1% to 99.9% by weight of the formulation.
  • pharmaceutically acceptable it is meant the carrier, diluent, excipients and salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • the formulations may be specially formulated for oral
  • compositions of this invention can be administered to humans and other mammals orally,
  • parenteral administration refers herein to modes of administration which include intravenous, intramuscular,
  • compositions of this invention for parenteral administration comprise sterile aqueous or non- aqueous solutions, dispersions, suspensions, or emulsions,
  • sterile powders which are reconstituted immediately prior to use into sterile solutions or suspensions.
  • suitable sterile aqueous and non- aqueous carriers, diluents, solvents or vehicles include water, physiological saline solution, ethanol, polyols (such as
  • glycerol as glycerol, propylene glycol, poly (ethylene glycol), and the like) , and suitable mixtures thereof, vegetable oils (such as olive oil) , and injectable organic esters such as ethyl oleate.
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by the
  • microorganisms is ensured by the inclusion of antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of injectable
  • formulations may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • subcutaneous or intramuscular injection This may be accomplished by the use of a liquid suspension or crystalline or amorphous material of low water solubility or by dissolving or suspending the drug in an oil vehicle.
  • a liquid suspension or crystalline or amorphous material of low water solubility or by dissolving or suspending the drug in an oil vehicle.
  • Injectable "depot” formulations of the compounds of this invention are made by forming microencapsulated
  • biodegradable polymers such as poly (lactic acid), poly (glycolic acid), copolymers of lactic and glycolic acid, poly (orthoesters) , and poly (anhydrides) these materials which are described in the art.
  • biodegradable polymers such as poly (lactic acid), poly (glycolic acid), copolymers of lactic and glycolic acid, poly (orthoesters) , and poly (anhydrides) these materials which are described in the art.
  • the rate of drug release can be controlled.
  • Injectable formulations are sterilized, for example, by filtration through bacterial-retaining filters, or by presterilization of the components of the mixture prior to
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such
  • the active component is mixed with at least one inert, pharmaceutically acceptable carrier such as sodium citrate, or dicalcium phosphate, and/or (a) fillers or extenders such as starches, lactose, glucose, mannitol, and silicic acid, (b) binding agents such as carboxymethyl- 750 cellulose, alginates, gelatin, poly (vinylpyrrolidine) , sucrose and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, silicates and sodium carbonate, (e) solution retarding agents such as paraffin,
  • pharmaceutically acceptable carrier such as sodium citrate, or dicalcium phosphate
  • fillers or extenders such as starches, lactose, glucose, mannitol, and silicic acid
  • binding agents such as carboxymethyl- 750 cellulose, alginates, gelatin, poly (viny
  • absorption accelerating agents such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerin monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid poly (ethylene glycols),
  • the dosage form may also contain buffering agents.
  • compositions of a similar type may also comprise the fill in soft or hard gelatin capsules using excipients
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can also be prepared with coatings or shells such as enteric coatings or other coatings well known
  • the coatings may contain opacifying agents or agents which release the active ingredient (s) in a particular part of the digestive tract, as for example, acid soluble coatings for release of the active ingredient (s) in the stomach, or base soluble
  • the active ingredient (s) may also be microencapsulated in a sustained-release coating, with the microcapsules being made part of a pill of capsule formulation.
  • Liquid dosage forms for oral administration of the compounds of this invention include solution, emulsions, suspensions, syrups and elixirs.
  • liquid formulations may include inert diluents commonly used in the art such as water or other
  • solvents such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, ground nut, corn, germ,
  • liquid oral formulations may also include adjuvants such as wetting agents,
  • Liquid suspension in addition to the active ingredient (s) may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol
  • compositions for rectal or intravaginal administration are prepared by mixing one or more compounds of the present
  • suitable non-irritating excipients such as cocoa butter, polyethylene glycol or any suppository wax which is a solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active component (s) .
  • suitable non-irritating excipients such as cocoa butter, polyethylene glycol or any suppository wax which is a solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active component (s) .
  • Compounds of the present invention may also be administered in the form of liposomes. As is know in the
  • liposomes are generally derived from phospholipids or other lipid substances.
  • Lipososome formulations are formed by mono- or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, pharmaceutically acceptable, and metabolizable lipid capable
  • the present compositions in liposome form can contain, in addition to one or more active compounds of the present invention, stabilizers, excipients, preservatives, and the like.
  • the preferred lipids are phospholipids and the phosphatidyl cholines 825 (lecithins), both natural and synthetic.
  • control comprised the vehicle employed in combination with the active compounds.
  • Example 15 is at least as effective, or more effective than tamoxifen as an agent for the inhibition or prevention of breast cancer.
  • administering is a useful method for the prophylaxis, prevention or inhibition of breast tumor formation.
  • the term "effective amount” means an amount of compound of the present invention which is capable of inhibiting or preventing breast tumor formation.
  • the specific dose of a compound administered according to this invention is determined by the particular circumstances surrounding each situation including, for example, the potency of the compound administered, the route of administration, the prior medical history of the patient, and the pathological condition being treated.
  • 910 daily dose will contain a nontoxic dosage level of from about 5 mg to about 600 mg/day of a compound of the present invention. Preferred daily doses generally will be from about 15 mg to about 80 mg/day.
  • the exact dose is determined, in accordance with the
  • Step b) Preparation of [ 6-methoxy-2- (4-methoxyphenyl) -3- ( 4-benzyloxy) phenoxy] benzo [b] thiophene
  • Step d) Preparation of [ 6-methoxy-3- [4- [2- (1-piperidinyl) - 1020 ethoxy] phenoxy] -2- (4-methoxyphenyl) ] benzo [b] - thiophene oxalate salt
  • thiophene thiophene (1.12 g, 2.97 mmol) in 7 mL of anhydrous N, N-dimethylformamide under N 2 was added 1025 cesium carbonate (3.86 g, 11.88 mmol).
  • Step d) Preparation of [ 6-Benzyloxy-2- (4-methanesulfonyloxyphenyl) ] benzo [b] thiophene
  • Step f) Preparation of [ 6-Benzyloxy-2- ( -methoxyphenyl) ] - benzo [b] thiophene
  • Step g) Preparation of [ 6-Benzyloxy-2- (4-methoxyphenyi; bromo] benzo [b] thiophene
  • Step h) Preparation of [ 6-Benzyloxy-2- (4-methoxyphenyl) -3- bro o] benzo [b] thiophene- (S-oxide)
  • Step k) Preparation of [ 6-Hydroxy-3- [4- [2- ( 1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) ]benzo [b] - 1495 thiophene
  • Step c) [ 6-Methoxy-2- (4-benzyloxyphenyl) -3-bromo] benzo [b] - 1580 thiophene- (S-oxide)
  • active ingredient 1655 means a compound of formula I, or a salt or solvate thereof.
  • Polyvinylpyrrolidone 4 (as 10% solution in water)
  • Talc 1 The active ingredient, starch, and cellulose are passed 1670 through a No . 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°-60° C and passed through a No . 18 mesh U.S. sieve.
  • the sodium 1675 carboxymethyl starch, magnesium stearate, and talc previously passed through a No . 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
  • the medicament is passed through a No.45 mesh U.S. 1685 sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume. 1690 Formulation Example 5
  • the active ingredient is mixed with ethanol and the
  • Active ingredient 250 Saturated fatty acid 2, 000 glycerides
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimal necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
  • the solution of the above ingredients is intravenously administered to a patient at a rate of about 1 mL per minute .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

Cette invention a trait à une méthode de prophylaxie du carcinome mammaire chez une patiente consistant à administrer à celle-ci une quantité efficace du point de vue thérapeutique d'un composé de la structure (I) dans laquelle R1 et R2 représentent, de manière indépendante, un hydroxy ou un alcoxy comportant de u à quatre atomes de carbone, R3 et R4 représentant, de manière indépendante, un méthyle ou un éthyle ou bien R3 et R4 pris avec l'atome d'azote auquel ils sont rattachés, constituent un noyau pyrrolidino, pyrrolidino-méthyle, pyrrolidino-diméthyle, pipéridino, morpholino ou hexaméthylène-imino.
EP98915368A 1997-04-09 1998-04-07 Prophylaxie du carcinome mammaire au moyen de modulateurs selectifs du recepteur des oestrogenes Withdrawn EP0975628A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US4311897P 1997-04-09 1997-04-09
US43118P 1997-04-09
PCT/US1998/006989 WO1998045286A1 (fr) 1997-04-09 1998-04-07 Prophylaxie du carcinome mammaire au moyen de modulateurs selectifs du recepteur des oestrogenes

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EP0975628A1 true EP0975628A1 (fr) 2000-02-02
EP0975628A4 EP0975628A4 (fr) 2001-03-21

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EP (1) EP0975628A4 (fr)
JP (1) JP2001518897A (fr)
KR (1) KR20010006215A (fr)
CN (1) CN1259945A (fr)
AU (1) AU6957398A (fr)
CA (1) CA2286207A1 (fr)
EA (1) EA199900910A1 (fr)
HU (1) HUP0001845A2 (fr)
ID (1) ID23653A (fr)
IL (1) IL132279A0 (fr)
NO (1) NO994902L (fr)
PL (1) PL336206A1 (fr)
TR (1) TR199903244T2 (fr)
WO (1) WO1998045286A1 (fr)
ZA (1) ZA982818B (fr)

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US6610706B1 (en) 1999-07-29 2003-08-26 Eli Lilly And Company Crystalline form of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b]thiophene hydrochloride
US6653479B1 (en) 1999-07-29 2003-11-25 Eli Lilly And Company Crystalline form of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4-methoxyphenyl)benzo[b] thiophene hydrochloride
NZ591955A (en) 2007-10-16 2011-10-28 Repros Therapeutics Inc Trans-clomiphene for diabetes mellitus type 2
ES2681023T3 (es) 2012-02-29 2018-09-11 Repros Therapeutics Inc. Terapia de combinación para tratar el déficit de andrógenos
AU2014219283C1 (en) 2013-02-19 2016-10-27 Novartis Ag Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders
GB201311888D0 (en) * 2013-07-03 2013-08-14 Glaxosmithkline Ip Dev Ltd Novel compounds
EP3373967B9 (fr) 2015-11-10 2023-10-04 Paracrine Therapeutics AB Traitement d'un cancer du sein négatif pour er à l'aide d'un inhibiteur du pdgf-cc et d'un anti- strogène

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US5510357A (en) * 1995-02-28 1996-04-23 Eli Lilly And Company Benzothiophene compounds as anti-estrogenic agents
SG90193A1 (en) * 1995-02-28 2002-07-23 Lilly Co Eli Benzothiophene compounds, intermediates, compositions, and methods
US5731342A (en) * 1996-02-22 1998-03-24 Eli Lilly And Company Benzothiophenes, formulations containing same, and methods

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FUCHS-YOUNG ET AL: "Preclinical demonstration of specific and potent inhibition of mammary tumor growth by new selective estrogen receptor modulators (SERMs" PROCEEDINGS OF THE ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH,US,PHILADELPHIA, AACR, vol. 38, March 1997 (1997-03), page 573 XP002111820 *
MASAHIKO SATO ET AL: "RALOXIFENE: A SELECTIVE ESTROGEN RECEPTOR MODULATOR" JOURNAL OF BONE AND MINERAL METOBOLISM,XX,XX, vol. 12, no. SUPPL. 02, 1994, pages S09-S20, XP000564019 *
See also references of WO9845286A1 *
TERMINE JOHN D: "Raloxifene HCL: A tissue selective estrogen receptor modifier (SERM) for replacement therapy in postmenopausal women." WOMEN'S HEALTH AND MENOPAUSE: RISK REDUCTION STRATEGIES., pages 315-320, XP000973248 2nd International Symposium on Women's Health in Menopause;Florence, Italy; December 5-8, 1996, Kluwer Law International;Kluwer Academic Publishers P. O. Box 85889, 2508, The Hague, Netherlands; 101 Phillip Drive, Norwell, Massachusetts 02061, USA ISBN: 0-7923-4697-1 *

Also Published As

Publication number Publication date
JP2001518897A (ja) 2001-10-16
CA2286207A1 (fr) 1998-10-15
NO994902D0 (no) 1999-10-08
ID23653A (id) 2000-05-11
ZA982818B (en) 1999-10-04
NO994902L (no) 1999-12-07
CN1259945A (zh) 2000-07-12
IL132279A0 (en) 2001-03-19
EA199900910A1 (ru) 2000-04-24
KR20010006215A (ko) 2001-01-26
AU6957398A (en) 1998-10-30
TR199903244T2 (xx) 2000-05-22
EP0975628A4 (fr) 2001-03-21
HUP0001845A2 (hu) 2001-06-28
WO1998045286A1 (fr) 1998-10-15
PL336206A1 (en) 2000-06-05

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