WO2001027129A1 - Glycosides et glycosides orthoesters de raloxifene, analogues et leurs utilisations - Google Patents

Glycosides et glycosides orthoesters de raloxifene, analogues et leurs utilisations Download PDF

Info

Publication number
WO2001027129A1
WO2001027129A1 PCT/GB2000/003864 GB0003864W WO0127129A1 WO 2001027129 A1 WO2001027129 A1 WO 2001027129A1 GB 0003864 W GB0003864 W GB 0003864W WO 0127129 A1 WO0127129 A1 WO 0127129A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound according
alkyl
prophylaxis
group
treatment
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.)
Ceased
Application number
PCT/GB2000/003864
Other languages
English (en)
Inventor
Michael Francis Holick
Halasya Ramanathan
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.)
STRAKAN Ltd
Kyowa Kirin International PLC
Original Assignee
STRAKAN Ltd
Kyowa Kirin International PLC
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
Application filed by STRAKAN Ltd, Kyowa Kirin International PLC filed Critical STRAKAN Ltd
Priority to AU76739/00A priority Critical patent/AU7673900A/en
Publication of WO2001027129A1 publication Critical patent/WO2001027129A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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 invention relates to derivatives of raloxifene and its analogues and the use thereof to treat conditions that are treatable with raloxifene and its analogues.
  • Raloxifene [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] ⁇ 4-[2-(l-piperidinyl)ethoxy]phenyl ⁇ methanone
  • its analogues and derivatives have proven useful in treating a number of conditions.
  • bone loss a number of conditions.
  • hypercholesteraemia and cancer c.f U.S. Patent Nos. 4,418,068, 5,393,763, 5,457,117, 5,478,847, 5,567,820, 5,641,790, 5,731,342, and 5,747,510).
  • US-A-5, 563,054, entitled “Process for Preparation ofBenzo[b]thiophene Glucuronides” describes a biotransformation process for the production of benzothiophene glucuronides from a benzothiophene (e.g., raloxifene) using Streptomyces sp. A93017.
  • US-A-5, 567, 820, entitled “Glucopyranoside Benzothiophenes” describes the chemical synthesis of benzothiophene glucuronides.
  • U.S. Patent Nos. 5,972,383 and 5,811,120 disclose that a particularly useful salt of raloxifene is the hydrochloride.
  • the aqueous solubility of raloxifene hydrochloride is poor, which somewhat limits its bioavailability.
  • These patents teach that one can overcome the limited bioavailability of raloxifene hydrochloride by administering it as part of a pharmaceutical composition comprising a hydrophilic carrier composition.
  • US-A-5,612,317 discloses methods of treating and preventing osteoporosis and alleviating the symptoms of menopause by administering an oestrogen glycoside, or oestrogen orthoester glycoside.
  • US-A-5, 508,392 discloses methods of treating and preventing osteoporosis by administering a vitamin D glycoside or vitamin D orthoester glycoside, or an analogue thereof.
  • raloxifene has been found to be useful in this area, but suffers because it has very low bioavailabilty.
  • glycosides and orthoester glycosides of raloxifene and its analogues provide higher bioavailability of the parent compound.
  • the present invention provides glycosides and orthoester glycosides of raloxifene and analogues thereof.
  • the present invention relates to a compound of Formula (I):
  • X, X' and X" are each the same or different and are O or S;
  • y is an integer from 1 to 6, inclusive;
  • R and R are independently hydrogen, -C ⁇ - alkyl, -C 3- cycloalkyl, -C ⁇ -7 alkyl-Y or phenyl, or, together, form a lower alkylene, a lower heteroalkylene, a lower alkenylene or lower heteroalkenylene group having from 3 to 6 atoms; and
  • Y is halogen, H, alkylcarbonyloxy, formyloxy or formyl;
  • R 3 and R 4 are the same or different and each represents H, halo, hydroxy, lower alkyl, lower hydroxyalkyl, lower haloalkyl or lower alkoxy group, or -OQ, wherein Q is a straight or branched chain glycosidic residue or glycosidic orthoester residue, or amino derivative thereof, provided that at least one of the groups Q is a glycoside or orthoester glycoside or amino derivative thereof;
  • the compounds of the invention exhibit higher plasma levels of the active, de-glycosylated compound than raloxifene administered alone. Thus, less of the compound needs be administered than with raloxifene alone, and it is easier to achieve useful levels of the parent compound in the serum.
  • glycosides and orthoester glycosides of the present invention yield the active compound only after passing through the liver, unlike raloxifene, which suffer substantial first-pass degradation in the liver before reaching the general circulation.
  • the compounds of the present invention serve as protected precursors of the active raloxifene or analogue.
  • the glycoside or orthoester glycoside group is cleaved in situ to yield the active compound.
  • the glycoside grouping is cleaved before the raloxifene or analogue can be metabolised, thereby protecting the active compound from first pass metabolism in the liver and making it available in the general circulation.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier therefor.
  • the invention also relates to a method for treating or preventing a condition selected from the group consisting of hypercholesteraemia, bone loss, oestrogen dependent cancer, and androgen dependent cancer, comprising administering to an animal having said condition an effective amount of a compound of the present invention.
  • CNS disorders such as Alzheimer's and schizophrenia.
  • the present invention is a significant advance in the art, as the bioavailability of the glycosides and orthoester glycosides of raloxifene and its analogues can be greatly improved relative to raloxifene and its salts.
  • the active compounds are released in the body, e.g. the liver, where the glycosides and ortho ester glycosides are cleaved.
  • the increased bioavailability of the glycosides and orthoester glycosides of raloxifene require a lower dosage of the drug to be administered.
  • the glycosides and orthoester glycosides can be more easily formulated due to their greater hydrophilicity.
  • the preferred route of administration is per os.
  • alkyl refers to a straight or branched chain, saturated, hydrocarbon group having from 1 to 7 carbon atoms, unless otherwise indicated.
  • the term “lower alkyl” is used herein to indicate an alkyl group having from 1 to 4 carbon atoms, unless otherwise indicated.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, n-pentyl, 2-methylpentyl, n- hexyl, 4-mefhylhexyl, 3-ethylpentyl, and n-heptyl.
  • haloalkyl is defined herein as an alkyl group having one or more halo substituents.
  • the halo substituents are preferably chosen from fluorine, chlorine, bromine and iodine.
  • alkoxy refers to the group “alkyl-O-,” wherein “alkyl” includes any of the Ci to C 4 alkyl groups mentioned above, which includes by way of example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy and the like.
  • cycloalkyl is defined herein to include cyclic hydrocarbon radicals having from 3 to 7 ring carbon atoms. Some exemplary cycloalkyl radicals include the cyclopropyl, cyclobutyl, cyclobutyl, and cyclopentyl groups. A preferred cycloalkyl group is cyclohexyl.
  • aryl alone or in combination, is defined herein as a wholly unsaturated, optionally substituted, monocyclic or polycyclic group, having from 6 to 14 carbon atoms, preferably a monocyclic or bicyclic group, e.g., phenyl or naphthyl.
  • Substituted aryl groups may be substituted, for example, with one or more and, in particular, one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkanoyl, alkylthio, alkylsulphinyl and alkylsulphonyl groups.
  • Some exemplary aryl groups include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-iodophenyl, 2-methylphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-trifluoromethylphenyl, 4- nitrophenyl, 3-acetoxyphenyl, 4-acetylaminophenyl, 2-methylthiophenyl, 8- hydroxynaphthyl, 6-isopropylnaphthyl, and the like.
  • aralkyl refers to the group “-alkylaryl,” wherein “alkyl” includes any of the Ci to C alkyl groups mentioned above and “aryl” includes any of the monocyclic or polycyclic aromatic groups mentioned above.
  • heteroaryl is defined herein as for aryl above, but containing one or more heteroatoms in place of one or more carbon atoms.
  • the heterocycle will be 5- or 6- membered ring containing one, two or three, preferably one or two, heteroatoms, to which a carbocyclic, especially monocyclic aryl, group may be attached.
  • the heterocyclic, aromatic group, or heteroaryl, optionally carrying a fused benzene ring, for example, may optionally be substituted.
  • Preferred substituents are selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulphinyl and alkylsulphonyl. There may be one or more substituents and, in particular, one to three substituents.
  • halogen is defined herein to include fluorine, chlorine, bromine and iodine.
  • linear and cyclic heteroalkyl are defined in accordance with the term “alkyl” with the suitable replacement of carbon atoms with a heteroatom, such as nitrogen, oxygen or sulphur, in a manner sufficient to render a chemically stable species.
  • X represents a sulphur atom, so that the core bicyclic structure is a benzothiophene.
  • X' and X" may be the same or different, but it is preferred that both represent oxygen atoms.
  • the integer y is suitably 1, 2, 3 or 4, with the group -(CH 2 ) y - preferably being ethylene or propylene, especially ethylene.
  • R 1 and R 2 are C alkyl, then it is preferred that they are either methyl or ethyl, and it is preferred that they are the same.
  • R 1 and R 2 together with the nitrogen atom to which they are attached, form a heterocyclic ring, then it is preferred that this be selected from piperidinyl, pyrrolidinyl, morpholinyl, and 1-hexamethyleneiminyl, especially piperidinyl and pyrrolidinyl, particularly piperidinyl.
  • R 3 and R 4 represents a group other than a glycoside, then it is preferred that this group is H, methyl or iodo, especially hydrogen.
  • Q is a glycosidic residue
  • Q is a glycosidic orthoester residue, then it is preferred that it have the Formula (II):
  • A' represents a glycofuranosyl or glycopyranosyl ring or amino derivative thereof
  • R is hydrogen, lower C alkyl, C 7- ⁇ o aralkyl, phenyl; or phenyl substituted by chloro, fluoro, bromo, iodo, lower C M alkyl or lower C M alkoxy; or naphthyl; and
  • R b is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue.
  • At least one group Q is a glucopyranoside residue.
  • R and R together with the nitrogen atom to which they are attached, form a heterocyclic ring.
  • a preferred group of compounds is those of Formula (la):
  • R 1 and R 2 are the same or different and are C M alkyl or R 1 and R 2 , together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from the group consisting of piperidinyl, pyrrolidinyl, morpholino, or 1 -hexamethyleneimino;
  • R 3 and R 4 are the same or different and are -OQ, wherein Q is hydrogen or a straight or branched chain glycosidic residue, or amino derivative thereof, containing 1-20 glycosidic units per residue, an orthoester glycoside moiety of the Formula (II); and pharmaceutically acceptable salts and esters thereof.
  • Especially preferred compounds of Formula (I) include, individually, and without limitation:
  • the compounds of the present invention may be used according to well known methods of using raloxifene and derivatives thereof, e.g. for use in treating conditions characterised by bone loss (e.g., post-menopausal osteoporosis, ovariectomy patients, senile osteoporosis, patients undergoing long-term treatment of corticosteroids, side effects from glucocorticoid or steroid treatment, patients suffering from Cushings's syndrome, gonadal dysgenesis, periarticular erosions in rheumatoid arthritis, osteoarthritis, Paget's disease, osteohalisteresis, osteomalacia, hypercalcaemia of malignancy, osteopenia due to bone metastases, periodontal disease, and hype arathyroidism), hypercholesteraemia, androgen and oestrogen dependent cancers (e.g., prostatic, uterine and breast cancer) and other conditions (See U.S.
  • bone loss e.g., post-meno
  • the compounds may also be used prophylactically to prevent the conditions enumerated above.
  • the compounds useful in the practice of the invention may contain at least one glycoside or orthoester glycoside residue on the A ring of the compound of Formula ⁇ .
  • the glycoside can typically comprise up to 20 glycosidic units. Preferred, however, are those having less than 10, most preferred, those having 3 or less glycosidic units. Specific examples are those containing 1 or 2 glycosidic units in the glycoside residue.
  • glycosidic units are meant glycopyranosyl or glycofuranosyl, as well as their amino sugar derivatives.
  • the residues may be homopolymers, random or alternating polymers, or block copolymers of these monomers.
  • the acyl groups are acetyl or propionyl.
  • R 5 groups are phenyl, nitrophenyl, halophenyl, lower alkyl substituted phenyl, lower alkoxy substituted phenyl and the like or benzyl, lower alkoxy substituted benzyl and the like.
  • glycopyranose or glycofuranose ring or amino derivative thereof may be fully or partially acylated or completely deacylated.
  • the completely or partially acylated glycoside is useful as a defined intermediate for the synthesis of the deacylated material.
  • glycopyranosyl structures glucose, mannose, galactose, gulose, allose, altrose, idose, or talose.
  • the preferred ones are derived from fructose, arabinose or xylose.
  • preferred diglycosides are sucrose, cellobiose, maltose, lactose, trehalose, gentiobiose, and melibiose.
  • the preferred ones may be raffmose or gentianose.
  • the preferred amino derivatives are N-acetyl-D-galactosamine, N-acetyl-D-glucosamine, N-acetyl-D- mannosamine, N-acetylneuraminic acid, D-glucosamine, lyxosylamine, D-galactosamine, and the like.
  • the individual glycosidic rings may be bonded by 1-1, 1-2, 1-3, 1-4, 1-5 or 1-6 bonds, most preferably 1-2, 1-4 and 1-6.
  • the linkages between individual glycosidic rings may be ⁇ or ⁇ .
  • Useful pharmaceutically acceptable salts include acid addition salts, e.g., salts with inorganic acids such as HC1, HBr, sulphuric, sodium hydrogen sulphate, phosphoric acid, sodium dihydrogen phosphate, and di sodium hydrogen phosphate, as well as salts with organic acids such as formic, acetic, benzoic, carbonic and the like.
  • inorganic acids such as HC1, HBr, sulphuric, sodium hydrogen sulphate, phosphoric acid, sodium dihydrogen phosphate, and di sodium hydrogen phosphate
  • organic acids such as formic, acetic, benzoic, carbonic and the like.
  • pharmaceutically acceptable salts may be obtained with an inorganic base such as an alkali or alkaline earth metal hydroxide [e.g. LiOH, NaOH, KOH, or Ca(OH) ] or an organic base such as choline hydroxide, spermidine, spermine, glucamine and the like.
  • the water soluble glycosidic derivatives of the aforementioned compounds may be obtained according to the general methods disclosed by Holick in U.S. Patent 4,410,515, the contents of which are fully incorporated by reference herein.
  • the glycosyl orthoester compounds may be obtained according to U.S. Patent 4,521,410, the contents of which are fully incorporated by reference herein.
  • Scheme I presents a general method of preparing the glycosyl derivatives of raloxifene.
  • the raloxifene mono-glycosides may be prepared using the mono-t-butyldimethylsilyl raloxifene derivatives described in US-A-5, 567, 820. Reaction of the mono-t-butyldimethylsilyl raloxifene with the glycosylating or orthoester glycosylating reagent according to U.S. Patent Nos. 4,410,515 and 4,521,410, followed by cleavage of the silyl ether with fluoride ion in methanol gives the mono-glycosyl and orthoester glycosyl raloxifene. The acyl groups may then be partially or fully removed to give the final product.
  • Any animal which may benefit from the compounds of Formula I, may be treated according to the present invention.
  • Preferred animals are mammals, e.g. humans, although the invention is not intended to be so limited.
  • the compounds of the invention can be administered in any appropriate pharmaceutically acceptable carrier.
  • the compounds of the invention may also be administered in any appropriate pharmaceutical carrier for parenteral, intramuscular, transdermal, intravenous, intranasal or inhalation administration. They can be administered by any means that achieve their intended purpose.
  • the dosage administered will depend on the age, health and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.
  • An exemplary systemic daily dosage is about 0.05 mg/kg to about 100 mg/kg of body weight, more preferably, from about 0.1 to about 80 mg/kg of body weight, most preferably, about 1-10 mg/kg of body weight of the glycoside or orthoester glycoside, in one or more dosages per day, or a pharmaceutically acceptable salt thereof, is effective to obtain the desired results.
  • the dosage is about 80 mg of raloxifene glucoside daily, although higher doses such as 100, 200 and 500 mg/daily may be given.
  • a low dose of raloxifene glycoside is administered, e.g.1 mg, 5 mg, 10 mg, or 30 mg per day.
  • the compounds can be employed in dosage forms such as tablets, capsules or powder packets, or liquid solutions, suspensions or elixirs for oral administration, as well as sterile liquid for formulations such as solutions or suspensions for parenteral use.
  • a lipid vehicle can be used in parenteral administration.
  • the compounds may also be administered via topical patches, ointments, gels, liposomes or other transdermal applications.
  • the active ingredient will ordinarily be present in an amount of at least 0.01% by weight based on the total weight of the composition, and not more than 90% by weight.
  • An inert pharmaceutically acceptable carrier is preferable such as 95% ethanol, vegetable oils, propylene glycols, saline buffers, sesame oil, etc. Reference is made to Remington 's Pharmaceutical Sciences, 18 l Edition, Gennaro et al. (eds.), 1990, for methods of preparing pharmaceutical compositions.
  • Topical formulations for transdermal, intranasal or inhalation administration may be prepared according to methods well known in the art.
  • the compounds may be applied in any of the conventional pharmaceutical forms.
  • the compounds may be administered as part of a cream, lotion, aerosol, ointment, powder, liposomes or drops.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • bases may include water and/or an oil such as liquid paraffin or a vegetable oil such as peanut oil or castor oil.
  • Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, wool-fat, hydrogenated lanolin, beeswax and the like.
  • Lotions may be formulated with an aqueous or oily base and will in general also include one or more of a stabilising agent, thickening agent, dispersing agent, suspending agent, thickening agent, colouring agent, perfume and the like.
  • Powders may comprise any suitable powder base including talc, lactose, starch and the like.
  • Drops may comprise an aqueous or non-aqueous base together with one or more dispersing agents, suspending agents, solubilising agents and the like.
  • Preferred liposomes are NOVASOMES sold by IGI, Inc. (Buena, NJ) and described in U.S. Pat. No.5,260,065.
  • compositions may further comprise one or more preservatives including bacteriostatic agents including methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride and the like.
  • the topical compositions comprise from about 0.0001%) to 10% by weight, preferably, 0.001 to 0.5% by weight, more preferably, 0.01 to 0.25% by weight.
  • the compounds may be administered using, for example, pressurised metered-dose inhalers which deliver aerosolised particles suspended in chlorofluorocarbon propellants such as CFC-11, CFC-12 or the non-chlorofluorocarbons, HFC- 134 A or HFC-227, with or without surfactants and suitable bridging agents; dry powder inhalers which are either breath activated or delivered by air or gas pressure such as the dry powder inhaler disclosed in PCT/US92/05225; the TURBOHALERTM (Astra Pharmaceutical Products, Inc.) or ROTAHALERTM (Allen & Hamburys) which may be used to deliver the compounds as a finely milled powder in large aggregates either alone or in combination with some pharmaceutically acceptable carrier (e.g. lactose); and nebulisers.
  • pressurised metered-dose inhalers which deliver aerosolised particles suspended in chlorofluorocarbon propellants such as CFC-11, CFC-12 or the non-chlorofluorocarbons, H
  • the compounds may also be administered in specific, measured amounts in the form of an aqueous solution or suspension by use of a pump spray bottle such as the bottles used to deliver VANCENASE AQTM Nasal Spray.
  • the aqueous solution or suspension may be prepared by admixing the compound with water and other pharmaceutically acceptable carriers. See PCT/US91/06249.
  • the aqueous suspensions may contain from about 0.001 to 100.0 mg, preferably, 0.1 to 10.0 mg of the compound per gram of suspension.
  • the aqueous solution or suspension may comprise auxiliaries and/or one or more excipients such as suspending agents (e.g. microcrystalline cellulose, sodium carboxymethyl-cellulose, hydroxypropylmethyl cellulose), hermectants (e.g.
  • glycerine or propylene glycol acids, bases or buffer substances for adjusting the pH (e.g. citric acid, sodium citrate, phosphoric acid, sodium phosphate as well as mixtures thereof); surfactants (e.g. polysorbate 80) and antimicrobial preservatives (e.g. benzalkonium chloride, phenethyl alcohol and potassium sorbate).
  • acids e.g. citric acid, sodium citrate, phosphoric acid, sodium phosphate as well as mixtures thereof
  • surfactants e.g. polysorbate 80
  • antimicrobial preservatives e.g. benzalkonium chloride, phenethyl alcohol and potassium sorbate.
  • the compounds may be administered either individually or as a mixture containing non-glycosylated, monoglycosylated, and/or bisglycosylated compounds, or a mixture of the corresponding orthoester glycosides.
  • the compounds are preferably provided substantially pure prior to formulation.
  • substantially pure encompasses compounds created by chemical synthesis and/or compounds substantially free of chemicals which may accompany the compounds in the natural state, as evidenced by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • Raloxifene was isolated from 60 mg tablets from Eli Lilly. 200 tablets were ground and suspended in methanol (1 litre) and ground sodium bicarbonate (50 g) was added. The mixture was refluxed for 3 hours and filtered hot. Methanol was stripped and acetone (1 litre) was added. The mixture was refluxed and filtered hot. The crystals were collected. The filtrate was recycled to obtain a yellow powder which was homogeneous by TLC. 2 : 1 (v/v) dichloromethane : methanol, containing traces of triethylamine, was used as eluent.
  • Raloxifene (0.5 g) was suspended in dry acetonitrile (10 ml) and silver silicate (1.6 g; freshly prepared from silver fluoride and sodium metasilicate) was added. Molecular sieves (3 g) were added to the above mixture and the contents were stirred under argon for 20 minutes. To the above suspension was added acetobromo- ⁇ -D-glucose (1.0 g; 2 equivalents; freshly recrystallised from diethylether). The mixture was warmed to 60°C for 2 hours. The mixture was filtered through a bed of silica gel (100 g) and eluted with dichloromethane and methanol mixture (1 : 1 v/v, containing traces of triethylamine). The yellow eluent was concentrated under vacuum. The yellowish crystals weighed 580 mg. The product was less polar than the starting material by TLC.
  • M + ions (methanol) were obtained at 803.93 amu and 1134.2 amu (expected values for M + ions are 803.76 and 1134.2 for the 2 possible monoglucosides [i.e.,
  • the yellowish crystals obtained above (0.5 g) were dissolved in hot methanol (30 ml), and Dowex-550 A-OH anion exchange resin (2 g) was added. The mixture was refluxed for 2 hours and filtered hot. The yellow filtrate, upon evaporation under vacuum, gave yellow crystals (340 mg).
  • the product was found to be a mixture of glucosides by NMR spectrum. One attempt to effect HPLC separation of this mixture was unsuccessful. The mass spectrum indicated the presence of the glucoside as a mixture of mono and doubly glucosylated products. The product was, however, insoluble in methanol, unlike the starting material.
  • Raloxifene glycoside mixture was dissolved in methanol and injected into the column. Three peaks were obtained @ 7.54, 9.28 & 11.98 minutes into the column. The peak at 11.98 minutes was the diglucoside and the two earlier peaks are the monogucoside derivatives of raloxifene. The fractions at 7.54, 9.28 and 11.98 were confirmed as raloxifene derivatives by UV absorption spectrophotometry ( ⁇ max 290 nm).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le raloxifène et ses analogues glycosides et glycosides orthoesters offrant une plus grande biodisponibilité de sérum du composé d'origine hydroxylé, utiles dans le traitement et la prévention de plusieurs pathologies pouvant être traitées avec un composé anti-oestrogénique ou un composé anti-androgène.
PCT/GB2000/003864 1999-10-08 2000-10-06 Glycosides et glycosides orthoesters de raloxifene, analogues et leurs utilisations Ceased WO2001027129A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76739/00A AU7673900A (en) 1999-10-08 2000-10-06 Glycosides and orthoester glycosides of raloxifene and analogues and the use thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US15814199P 1999-10-08 1999-10-08
US60/158,141 1999-10-08
US23157300P 2000-09-11 2000-09-11
US60/231,573 2000-09-11

Publications (1)

Publication Number Publication Date
WO2001027129A1 true WO2001027129A1 (fr) 2001-04-19

Family

ID=26854778

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/003864 Ceased WO2001027129A1 (fr) 1999-10-08 2000-10-06 Glycosides et glycosides orthoesters de raloxifene, analogues et leurs utilisations

Country Status (2)

Country Link
AU (1) AU7673900A (fr)
WO (1) WO2001027129A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6916791B2 (en) 1999-05-04 2005-07-12 Strakan Limited Androgen derivatives and uses thereof
US7425565B2 (en) 2002-05-09 2008-09-16 Cedars-Sinai Medical Center Use of benzothiopenes to treat and prevent prostate cancer

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0683170A1 (fr) * 1994-05-20 1995-11-22 Eli Lilly And Company Benzothiophènes de glucopyranoside
WO1996003995A1 (fr) * 1994-08-04 1996-02-15 Holick Michael F Procede d'administration d'×strogene
US5508392A (en) * 1992-12-29 1996-04-16 Holick; Michael F. Use of vitamin D glycosides, vitamin D orthoester glycosides, vitamin D analog glycosides and vitamin D analog orthoester glycosides for the treatment of osteoporosis
EP0735141A2 (fr) * 1995-03-31 1996-10-02 Eli Lilly And Company Procédé de préparation de benzo(b)thiophène glucuronides
WO1999007693A1 (fr) * 1997-08-11 1999-02-18 Eli Lilly And Company Benzothiophenes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5508392A (en) * 1992-12-29 1996-04-16 Holick; Michael F. Use of vitamin D glycosides, vitamin D orthoester glycosides, vitamin D analog glycosides and vitamin D analog orthoester glycosides for the treatment of osteoporosis
EP0683170A1 (fr) * 1994-05-20 1995-11-22 Eli Lilly And Company Benzothiophènes de glucopyranoside
US5567820A (en) * 1994-05-20 1996-10-22 Eli Lilly And Company Glucopyranoside benzothiophenes
WO1996003995A1 (fr) * 1994-08-04 1996-02-15 Holick Michael F Procede d'administration d'×strogene
EP0735141A2 (fr) * 1995-03-31 1996-10-02 Eli Lilly And Company Procédé de préparation de benzo(b)thiophène glucuronides
US5563054A (en) * 1995-03-31 1996-10-08 Eli Lilly And Company Process for preparation of benzo[B]thiophene glucuronides
WO1999007693A1 (fr) * 1997-08-11 1999-02-18 Eli Lilly And Company Benzothiophenes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DODGE J A ET AL: "Synthesis and estrogen receptor binding affinities of the major human metabolites of raloxifene (LY139481)", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,GB,OXFORD, vol. 7, no. 8, 22 April 1997 (1997-04-22), pages 993 - 996, XP004136171, ISSN: 0960-894X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6916791B2 (en) 1999-05-04 2005-07-12 Strakan Limited Androgen derivatives and uses thereof
US7425565B2 (en) 2002-05-09 2008-09-16 Cedars-Sinai Medical Center Use of benzothiopenes to treat and prevent prostate cancer

Also Published As

Publication number Publication date
AU7673900A (en) 2001-04-23

Similar Documents

Publication Publication Date Title
KR100647204B1 (ko) 글루코피라노실옥시벤질벤젠 유도체 및 그것을 함유하는의약조성물
US8987216B2 (en) Polysulfated glycosides and salts thereof
JP7335288B2 (ja) アミノグリコシド誘導体および遺伝性疾患の治療におけるその使用
CN103702670A (zh) 苷前体药物类似物的合成和应用
KR20050008658A (ko) 아포모르핀의 글리코시드 및 오르토에스테르 글리코시드유도체들, 유사체들 및 그것의 용도
JP2024509820A (ja) 相乗的カンナビノイドエステル、その塩及びその使用
HU225501B1 (en) Use of chalcone esters and complexes for producing pharmaceutical compositions against cancer and ii.typ estrogen receptor antagonist
JP2018528211A5 (fr)
RU2145598C1 (ru) Производные колхицина, способ их получения, фармацевтическая композиция
KR100306430B1 (ko) 콜히친골격화합물과그들의의약품으로서의용도및이들을함유한조성물
CA2484891A1 (fr) Conjugues comprenant un medicament agissant sur le systeme nerveux central, lequel medicament est lie a un acide glucuronique ou a une glucosamine par l'intermediaire d'une liaison amide, et utilisations correspondantes
NZ293243A (en) Use of optionally halogenated or sulphonated anthracycline (daunomycin, doxorubicia) derivatives to prepare medicaments for treating amyloidosis
WO2017118968A1 (fr) Dérivés d'aminoglycosides et leurs utilisations pour traiter les maladies génétiques
KR20200104352A (ko) 약물의 경구 생체이용률을 향상시키는 방법
WO2025165992A1 (fr) O-glycosylation chimique et glucuronidation de cannabinoïdes
US7217696B2 (en) Glycuronamides, glycosides and orthoester glycosides of fluoxetine, analogs and uses thereof
US20150105543A1 (en) Synthesis
KR100449580B1 (ko) 아자-안트라사이클리논유도체
US6548485B2 (en) Stable antitumor drug
WO2001027127A1 (fr) Glycosides de tamoxifene et d'analogues de tamoxifene et leurs utilisations
CN103608019A (zh) 抗肿瘤剂
US20050009759A1 (en) Derivatives of etoposide and analogs, and pharmaceutical compositions containing them
JP5307399B2 (ja) １３−デオキシアントラサイクリン類を調製するための組成物及び方法
US20090298784A1 (en) Isolation and structure of turbostatins 1-4
WO1991009044A1 (fr) Nouveaux derives de triacontanol-1

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP