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WO1996014090A1 - Compositions comprenant des carbazoles et des cyclodextrines - Google Patents

Compositions comprenant des carbazoles et des cyclodextrines Download PDF

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Publication number
WO1996014090A1
WO1996014090A1 PCT/EP1995/004295 EP9504295W WO9614090A1 WO 1996014090 A1 WO1996014090 A1 WO 1996014090A1 EP 9504295 W EP9504295 W EP 9504295W WO 9614090 A1 WO9614090 A1 WO 9614090A1
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WO
WIPO (PCT)
Prior art keywords
formula
cyclodextrin
group
composition according
compounds
Prior art date
Application number
PCT/EP1995/004295
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English (en)
Inventor
Jean Louis Mesens
Herman Maria Jozef Van Cauteren
Peter Putteman
Jozef Peeters
Original Assignee
Janssen Pharmaceutica N.V.
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Filing date
Publication date
Application filed by Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.
Priority to AU38463/95A priority Critical patent/AU3846395A/en
Publication of WO1996014090A1 publication Critical patent/WO1996014090A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin

Definitions

  • compositions comprising carbazoles and cyclodextrins
  • This invention relates to pharmaceutical compositions comprising carbazole derivatives and cyclodextrins, to processes of preparing such compositions, and to their use for the manufacture of medicaments.
  • Ri and R4 each independently represent a hydrogen atom or a Ci-6alkyl group; each R2 may be the same or different and represents an electron-withdrawing group; each R3 may be the same or different and represents an electron-withdrawing group; R5 is a group of formula
  • R6 is a halogen atom, a Ci-6alkyl group or a Ci-6alkyloxy group; m is zero or an integer 1 to 4; n is zero or an integer 1 to 3; and p is zero, 1 or 2; the pharmaceutically acceptable salts and solvates thereof, are interesting inhibitors of the enzyme 17,20-lyase and as such are useful ingredients in medicines that reduce androgen and/or oestrogen levels in mammals, including humans. These compounds, their pre ⁇ paration and characteristics are disclosed in WO-94/27989 (PCT appl. No. EP 94.01613 filed on May 19, 1994 and claiming priority of GB 9310635.9, filed 21 May 1993).
  • the carbazoles of formula (I) are only sparingly soluble in neutral aqueous solutions. Most of them hardly form acid addition salt forms and thus they are poorly soluble in acidic aqueous solutions, too. Moreover, the carbazoles of formula (I) decompose in highly acidic media (about pH 1). Consequently, there is a need for therapeutic compositions that allow one to administer meaningful dosages of the carbazole derivatives of formula (I) to the subjects to be treated. It has now been found that compositions of the carbazoles of formula (I), together with a cyclodextrin or a cyclodextrin derivative, and optionally one or more excipients or carriers as known in the art, lack the aforementioned bioavailability problem.
  • the present invention concerns pharmaceutical compositions comprising a compound of formula (I)
  • Ri and R4 each independently represent a hydrogen atom or a Ci-6alkyl group; each R2 may be the same or different and represents an electron-withdrawing group; each R3 may be the same or different and represents an electron-withdrawing group; R5 is a group of formula
  • R6 is a halogen atom, a Ci-6al yl group or a Ci-6alkyloxy group; m is zero or an integer 1 to 4; n is zero or an integer 1 to 3; and p is zero, 1 or 2; or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, a cyclodextrin or a cyclodextrin derivative as solubilizing agent, and optionally one or more pharmaceutical carriers or excipients.
  • the substituents R2 may each occupy any available position of the 5, 6, 7 or 8 positions.
  • the substituents R3 may each occupy any available position of the 1, 2, 3 or 4 positions, preferably the 1, 3 or 4 positions.
  • the group CHR4R5 may occupy any of the 1, 2, 3 or 4 positions, for example, the 1, 2 or 3 positions. Preferably the group CHR4R5 will be in the 2 position.
  • the invention provides compounds of formula (I a )
  • the substituent R6 may be attached to any carbon atom in the pyridyl ring, but preferably is attached in the 3, 4 or 5 positions.
  • formula (I) may contain a chiral centre. It is to be understood that formula (I) is intended to encompass all enantiomers and diastereoisomers of the compounds of the invention as well as mixtures thereof, including racemates.
  • Electron- withdrawing groups are well known to those skilled in the art and any such group may be employed.
  • groups include halogen atoms, such as fluorine, chlorine and bromine atoms, nitrile groups, nitro groups, trifluoromethyl groups, aldehydo groups, keto groups and carboxylic acid and ester groups and are preferably selected from fluorine atoms, chlorine atoms and nitrile groups.
  • Particularly preferred as compounds of formula (I) are those wherein each of R2 and R3 represents a fluorine atom.
  • R2 represents a fluorine atom and m is an integer 1 to 4.
  • Ci-6alkyl and Ci-6alkoxy groups may contain straight or branched chain alkyl groups, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, pentyl or hexyl groups, preferably Cl-4alkyl groups.
  • each of Ri and R4 may be a hydrogen atom or a methyl, ethyl, propyl or butyl group.
  • Rl and R4 are each preferably a hydrogen atom or a methyl group.
  • R5 is a pyridin-3-yl or pyridin-4-yl group.
  • R6 represents a fluorine atom, a methyl group or a methoxy group.
  • Rl and R4 each represent a hydrogen atom or a methyl group
  • R2 and R3 are fluorine atoms
  • R6 is a fluorine atom, a methyl group or a methoxy group
  • m is an integer 1 to 4
  • n is zero or an integer 1 to 3
  • p is zero, 1 or 2.
  • Ri and R4 each represent a hydrogen atom
  • R2 and R3 are fluorine atoms
  • R6 is a fluorine atom or a methyl or methoxy group and m
  • n and p each independently represent zero, 1 or 2.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, citrates, tartrates, maleates, fumarates, succinates, p-toluenesulphonates and methanesulphonates.
  • acid addition salts derived from inorganic and organic acids such as hydrochlorides, hydrobromides, sulphates, phosphates, citrates, tartrates, maleates, fumarates, succinates, p-toluenesulphonates and methanesulphonates.
  • Other suitable salts will be readily apparent to one skilled in the art Hydrochloride, sulphate, phosphate and citrate salts are especially preferred. Salts which are not pharmaceutically acceptable may be useful in the preparation of compositions according to the present invention.
  • cyclodextrin or a cyclodextrin derivative is the compound 2-fluoro-7-(3-pyridinylmethyl)-9H-carbazole mono- hydrochloride which has exceptionally high solubility and oral bio-availability.
  • the compounds according to the invention may be prepared by any process known in the art for the preparation of compounds of analogous structure.
  • Rj, R2, R3, R4, R5, R6» m, n and p are as defined for general formula (I) unless otherwise specified.
  • a compound of general formula (I) wherein Rj represents a hydrogen atom may be prepared from an intermediate of formula (II) by cyclisation.
  • reaction is conveniently effected in the presence of a suitable solvent, such as a hydrocarbon solvent, for example dodecane, or a halogenated solvent, such as dichlorobenzene, preferably at elevated temperature, for example 100 to 300°C, preferably 150 to 220°C.
  • a suitable solvent such as a hydrocarbon solvent, for example dodecane, or a halogenated solvent, such as dichlorobenzene, preferably at elevated temperature, for example 100 to 300°C, preferably 150 to 220°C.
  • a suitable solvent such as a hydrocarbon solvent, for example dodecane
  • a halogenated solvent such as dichlorobenzene
  • a hydrogen-donor e.g. ammonium formate
  • a catalyst such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal.
  • the reduction may be carried out in a solvent such as an alcohol e.g. methanol or ethanol (which may be aqueous), acetic acid, aqueous acetic acid, an ether e.g. dioxan, an ester e.g. ethyl acetate or an amide e.g. dimethylformamide, and conveniently at a temperature of from -10 to +50°C, preferably 20 to 30°C.
  • a solvent such as an alcohol e.g. methanol or ethanol (which may be aqueous), acetic acid, aqueous acetic acid, an ether e.g. dioxan, an ester e.g. ethyl acetate or an
  • reaction by treatment with a compound of formula HR5 (1,2,4-triazole) or the sodium salt thereof.
  • a compound of formula HR5 (1,2,4-triazole) or the sodium salt thereof.
  • the reaction is conveniently effected in a suitable solvent, e.g dimethylformamide.
  • reaction is conveniently effected in a non-polar solvent, such as a halogenated solvent, e.g. chloroform or tetrachloromethane, at a temperature of 20 to 80°C.
  • a non-polar solvent such as a halogenated solvent, e.g. chloroform or tetrachloromethane, at a temperature of 20 to 80°C.
  • Suitable palladium(O) catalyst such as tetrakis(triphenylphosphine) palladium (0) and a base, e g. sodium carbonate
  • a suitable aqueous solvent such as an alcohol, e.g. ethanol, an aromatic hydrocarbon, e.g. benzene, or an ether, e.g. dimethoxyethane, or an aqueous mixture of solvents.
  • Suitable atoms or groups represented by L include halogen atoms, e.g. bromine or iodine atoms, or a triflate group.
  • a compound of formula (I) may be prepared from a compound of
  • the deoxygenation reaction is effected using a suitable reducing agent such as hydrogen in the presence of a catalyst, such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal.
  • a catalyst such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal.
  • the reaction may conveniently be carried out in a solvent such as an alcohol, e.g. methanol or ethanol, which may be aqueous, in the presence of an acid, e.g. hydrochloric acid, preferably at elevated temperature, e.g. at the reflux temperature of the solvent or at elevated pressure.
  • General process (B) is particularly useful for the preparation of compounds of formula (I) wherein R5 is a pyridyl group.
  • reaction by reaction with compounds of formula Hal-R5 (XI) in the presence of a suitable base, such as an alkyllithium, e.g. n-butyllithium.
  • a suitable base such as an alkyllithium, e.g. n-butyllithium.
  • the reaction is conveniently effected in the presence of a suitable solvent such as an ether, e.g. diethyl ether, dimethoxyethane or tetrahydrofuran, or a mixture of solvents, suitably at low temperature, e.g. -90 to -50°C, preferably about -70°C.
  • Suitable oxidising agents will be readily apparent to one skilled in the art and include pyridinium chlorochromate, potassium dichromate in sulphuric acid and barium manganate.
  • the reaction may conveniently be effected in the presence of a solvent, e.g. a halogenated solvent such as dichloromethane.
  • reaction is conveniently effected in the presence of a suitable solvent, such as a hydrocarbon solvent, e.g. dodecane, or a halogenated solvent, e.g. dichloro- metiiane, preferably at elevated temperature, e.g. 100 to 300°C, preferably 150 to 220°C.
  • a suitable solvent such as a hydrocarbon solvent, e.g. dodecane, or a halogenated solvent, e.g. dichloro- metiiane, preferably at elevated temperature, e.g. 100 to 300°C, preferably 150 to 220°C.
  • reaction by treatment with sodium nitrite in the presence of a mineral acid, e.g. sulphuric acid, followed by sodium azide.
  • a mineral acid e.g. sulphuric acid
  • the reaction is conveniently effected in aqueous solution.
  • G represents a hydroxy protecting group by reduction using hydrogen or a hydrogen-donor, e.g. ammonium formate, in the presence of a catalyst, such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal and subsequent removal of the protecting group G.
  • a catalyst such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal and subsequent removal of the protecting group G.
  • the reduction may conveniently be carried out in a solvent such as an alcohol, e.g. methanol or ethanol, which may be aqueous, optionally in the presence of an acid, e.g. hydrochloric acid.
  • L represents a readily displaceable atom or group by reaction with a compound of formula (XVJT)
  • a suitable palladium (0) catalyst such as tetrakis(triphenylphosphine) palladium (0) and a base, e.g. sodium carbonate
  • a suitable aqueous solvent such as an alcohol, e.g. ethanol, an aromatic hydrocarbon, e.g. benzene, or an ether, e.g. dimethoxyethane, or an aqueous mixture of solvents preferably at elevated temperature.
  • Suitable atoms or groups represented by L include a halogen atom, e.g. a bromine or iodine atom, and a triflate group.
  • a compound of formula (I) wherein Rl represents a hydrogen atom may be alkylated using conventional techniques.
  • the reaction may be effected using a suitable alkylating agent such as an alkyl halide, alkyl tosylate or dialkylsulphate.
  • the reaction may conveniently be carried out in an inert organic solvent such as an amide, e.g. dimethylformamide, or an ether, e.g. tetrahydrofuran, preferably in the presence of a base.
  • Suitable bases include, for example, alkali metal hydrides, e.g. sodium hydride, alkali metal carbonates, e.g.
  • alkylation reaction is conveniently effected at a temperature offrom 25 to lOO°C.
  • a compound of formula (I) according to the invention or a salt thereof may be prepared by subjecting a protected derivative of formula (I) or a salt thereof to reaction to remove the protecting group or groups.
  • a protected derivative of formula (I) or a salt thereof it may have been necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.
  • Such protection may be effected in conventional manner, for example as described in 'Protective Groups in Organic Chemistry' Ed. J.F.W. McOmie (Plenum Press 1973) or 'Protective Groups in Organic Synthesis' by T. W. Greene (John Wiley and Sons 1981).
  • the group NRi may be protected for example with a conventional amino protecting group.
  • groups may include for example aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as tosyl, N-benzyloxycarbonyl or t-butoxycarbonyl.
  • an aralkyl group such as benzyl
  • a catalyst e.g. palladium on charcoal
  • an acyl group such as t-butoxycarbonyl may be removed by cleavage with, for example, hydrogen chloride in dioxan or sodium methoxide in methanol.
  • a compound of the invention for example as an acid addition salt
  • this may be achieved by treating the free base of general formula (I) with an appropriate acid, preferably with an equivalent amount
  • Solvates of the compounds of the invention may be prepared by crystallisation from or evaporation of an appropriate solvent solution of the compounds of formula (I). Separation of enanuomers of formula (I) may be carried out in conventional manner, for example by resolution of racemic mixtures e.g. using chiral HPLC techniques or by stereospecific synthesis from isomerically pure starting material or any convenient intermediate, for example as described in Stereochemistry of Carbon Compounds by E.L. Eliel (McGraw Hill, 1962) and Tables of Resolving Agents by S.H. Wilen.
  • the compounds according to the invention are potent and selective inhibitors of the enzyme steroidal 17,20-lyase, which is a key enzyme involved in the conversion of C21 -steroids (e.g. pregnenolone) into androgens (e.g. testosterone) and oestrogens (e.g. oestradiol).
  • C21 -steroids e.g. pregnenolone
  • androgens e.g. testosterone
  • oestrogens e.g. oestradiol
  • the 17,20-lyase-inhibiting activity of the compounds of formula (I) can be demonstrated in vitro by their ability to inhibit the conversion of 17- ⁇ -hydroxypregnenolone into dehydroepiandrosterone by human testicular 17,20-lyase, and of 17- ⁇ -hydroxypro- gesterone into androstenedione by rat testicular 17,20-lyase.
  • compositions of the invention can thus be used in the treatment of androgen- and/or oestrogen-dependant diseases such as malignant and benign diseases of the breast, endometrium, ovary, prostate and pancreas. These diseases include cancer of the prostate, breast and endometrium, prostatic hypertrophy and hyperplasia, fibrocystic breast disease, endometriosis and polycystic ovarian disease.
  • the compounds of formula (I) are also useful in the treatment of Cushing's syndrome, gynecomastia, premature labour, precocious puberty, female hirsutism, premenstrual syndrome, male pattern baldness and acne.
  • the compounds of formula (I) will be particularly useful in the treatment of prostate cancer.
  • cyclodextrins for use in the present compositions are ⁇ -, ⁇ -, ⁇ -cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C ⁇ _5alkyl, particularly methyl, ethyl or isopropyl, e.g.
  • ⁇ -CD randomly methylated ⁇ -CD
  • hydroxyC ⁇ _6alkyl particularly hydroxyethyl, hydroxypropyl or hydroxybutyl
  • carboxyC ⁇ _6alkyl particularly carboxymethyl or carboxyethyl
  • Ci ⁇ alkylcarbonyl particularly acetyl
  • C ⁇ -6alkylcarbonyloxyC ⁇ -6alkyl particularly 2-acetyloxypropyl.
  • complexants and/or solubilizers are ⁇ -CD, randomly methylated ⁇ -CD, 2,6-dimethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxypropyl- ⁇ -CD and (2-carboxymethoxy)propyl- ⁇ -
  • mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy- propyl and hydroxyethyl.
  • the average molar substitution is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose.
  • the M.S.value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (LR).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • LR infrared spectroscopy
  • slighUy different values may be obtained for one given cyclodextrin derivative.
  • the M.S. as determined by mass spectrometry is in the range of 0.125 to 10, in particular of 0.3 to 3, or from 0.3 to 1.5.
  • the M.S. ranges from about 0.3 to about 0.8, in particular from about 0.35 to about 0.5 and most particularly is about 0.4.
  • M.S. values determined by NMR or LR preferably range from 0.3 to 1, in particular from 0.55 to 0.75.
  • the average substitution degree refers to the average number of substituted hydroxyls per anhydroglucose unit
  • the D.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (LR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative.
  • the D.S. as determined by MS is in the range of 0.125 to 3, in particular of 0.2 to 2 or from 0.2 to 1.5.
  • the D.S. ranges from about 0.2 to about 0.7, in particular from about 0.35 to about 0.5 and most particularly is about 0.4.
  • D.S. values determined by NMR or LR preferably range from 0.3 to 1, in particular from 0.55 to 0.75.
  • ⁇ - and ⁇ -cyclodextrin hydroxyalkyl derivatives for use in the compositions according to the present invention are partially substituted cyclodextrin derivatives wherein the average degree of alkylation at hydroxyl groups of different positions of the anhydroglucose units is about 0% to 20% for the 3 position, 2% to 70% for the 2 position and about 5% to 90% for the 6 position.
  • the amount of unsubstituted ⁇ - or ⁇ -cyclodextrin is less than 5% of the total cyclodextrin content and in particular is less than 1.5%.
  • Another particularly interesting cyclodextrin derivative is randomly methylated ⁇ -cyclodextrin.
  • cyclodextrin derivatives for use in the present invention are those partially substituted ⁇ -cyclodextrin ethers or mixed ethers having hydroxypropyl, hydroxyethyl and in particular 2-hydroxypropyl and/or 2-(l -hydroxypropyl) substituents.
  • the most preferred cyclodextrin derivative for use in the compositions of the present invention is 2-hydroxypropyl- ⁇ -cyclodextrin having a M.S. (as determined by mass spectrometry) in the range of from 0.35 to 0.50 and containing less than 1.5% unsubstituted ⁇ -cyclodextrin.
  • M.S. values determined by NMR or LR preferably range from 0.55 to 0.75.
  • cyclodextrins can be prepared according to procedures described in US-3,459,731, EP-A-0,149,197, EP-A-0, 197,571, US-4,535,152, WO-90/12035 and GB-2, 189,245.
  • Other references describing cyclodextrins for use in the compositions according to the present invention, and which provide a guide for the preparation, purif ⁇ - cation and analysis of cyclodextrins include the following : "Cyclodextrin Technology” by J ⁇ zsef Szejtli, Kluwer Academic Publishers (1988) in the chapter Cyclodextrins in Pharmaceuticals; "Cyclodextrin Chemistry” by M.L.
  • compositions according to the present invention may consist of only the carbazole derivative of formula (I) and the cyclodextrin or cyclodextrin derivative.
  • Such form is particularly useful for reconstitution with water, saline or an aqueous solution of the cyclodextrin; but also for preparing the pharmaceutical compositions described in the following paragraphs.
  • This solid form can conveniendy be prepared by lyophilization of an aqueous solution of the active ingredient and the cyclodextrin.
  • said solid form can also be prepared by extrusion of the components, in particular by melt extrusion.
  • the pharmaceutical compositions according to the present invention comprise one or more excipients or carriers as known in the art.
  • the pharmaceutical compositions are adapted for oral, rectal, vaginal, topical, parenteral (including intramuscular, subcutaneous and intravenous) or implant administration, or in a form suitable for administration by inhalation or insufflation.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units.
  • the pharmaceutical compositions may take the form of solid dose forms, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means, optionally with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methylcellulose, hydroxypropyl methylcellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g. sorbitol syrup, methylcellulose, hydroxypropyl methylcellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily
  • an acidic aqueous medium there may be used an acidic aqueous medium.
  • the acidity of said carrier derives from a pharmaceutically acceptable acid such as described above in the definition of 'salts', in particular hydrochloric acid, phosphoric acid, citric acid or mixture thereof.
  • the bioavailability of the carbazole derivative and the stability of the liquid formulations are affected contrariwise by increasing acidity. An optimum effect can be obtained at pH 2.0 ⁇ 0.1 : that is, at this pH value, a sufficiently bioavailable formulation is obtainable, the stability of which is entirely satisfactory.
  • Taste masking can be obtained by the use of adjuvants, namely pharmaceutically acceptable sweeteners and/or flavours.
  • adjuvants namely pharmaceutically acceptable sweeteners and/or flavours.
  • Sweeteners are usually the more important additives in the low-dosage formulations, whereas the flavours are usually more important in the high- dosage formulations.
  • Pharmaceutically acceptable sweeteners comprise preferably at least one intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose (4, ,6'-trichloro-4, ,6'-trideoxyj ⁇ /flctosucrose), preferably saccharin, sodium or calcium saccharin, and optionally a bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.
  • intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose
  • Intense sweeteners are conveniently employed in low concentrations.
  • the concentration may range from 0.04% to 0.1 % (w/v) based on the total volume of the final formulation, and preferably is about 0.06% in the low-dosage formulations and about 0.08% in the high-dosage ones.
  • the bulk sweetener can effectively be used in larger quantities ranging from about 10% to about 35%, preferably from about 10% to 15% (w/v).
  • the cyclodextrin derivative behaves as a bulk sweetener and none of the aforementioned bulk sweeteners needs to be added.
  • the pharmaceutically acceptable flavours which can mask the bitter tasting ingredients in the low-dosage formulations are preferably fruit flavours such as cherry, raspberry, black currant or strawberry flavour. A combination of two flavours may yield very good results.
  • stronger flavours may be required such as Caramel Chocolate flavour, Mint Cool flavour, Fantasy flavour and the like pharmaceutically acceptable strong flavours.
  • Each flavour may be present in the final composition in a concentration ranging from 0.05% to 1% (w/v). Combinations of said strong flavours are advantageously used.
  • a flavour is used that does not undergo any change or loss of taste and colour under the acidic conditions of the formulation.
  • a low-dosage oral formulation according to the present invention typically comprises from about 2% to about 20% (w/v), preferably about 5% (w/v) of the cyclodextrin and about 0.1% (w/v) active ingredient.
  • a high-dosage formulation typically comprises from about 10% to about 60% (w/v), preferably from about 20% (w/v) to about 30% (w/v) of the cyclodextrin derivative and about 0.5% (w/v) active ingredient.
  • a very high-dose oral formulation according to the present invention comprises from about 5% to about 20%, preferably about 10% (w/v) of the cyclodextrin and from 0.5% to about 2.5%, in particular about 1% (w/v) of 2-fluoro-7-(3-pyridinylmethyl)-9H- carbazole monohydrochloride.
  • Very high-dose formulations are particularly suitable for treating patients suffering from those conditions wherein it is essential to maintain constant, high plasm levels of the carbazole drug and the amount of cyclodextrin carrier administered approaches the maximum oral tolerability.
  • Suitable oral formulations can be prepared following the steps :
  • an alcoholic co-solvent may be employed in the formulations according to the present invention.
  • the dissolution of the active ingredient in an aqueous acidic cyclodextrin medium may be slow.
  • Addition of the alcoholic co-solvent in the range of about 1 % (v/v) to about 20% (v/v), preferably about 10% (v/v), usually increases the dissolution rate of the active agent in an aqueous acidic cyclodextrin medium considerably and thus may shorten and simplify the production process.
  • the pharmaceutical compositions may take the form of buccal or sub-lingual tablets, drops or lozenges formulated in conventional manner.
  • the compounds of the invention may be formulated as creams, gels, ointments or lotions or as transdermal patches.
  • Such compositions may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilising, dispersing, suspending, and/or colouring agents.
  • the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt.
  • the compounds of the invention may be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multidose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as isotonizing, suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water before use.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the form of drops.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch
  • compositions described above may be presented in a conventional manner associated with controlled release forms.
  • compositions according to the invention are suitable for oral, rectal or topical administration.
  • compositions as claimed are well known in the art of pharmacy and are characterized in that the active ingredient, the cyclodextrin or cyclodextrin derivative, and optionally the excipient, are intimately mixed with one another. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • compositions may advantageously be presented in discrete dose units, especially in unit dosage forms.
  • a convenient unit dose formulation contains the active ingredient in an amount of from 10 to 200 mg, preferably an amount of from 50 to 100 mg.
  • a suitable dose will be in the range of from about 1 to about 500 mg per day, preferably in the range of 50 to 400 mg per day, most preferably in the range of 100 to 300 mg per day.
  • the suitable dose will be in the range of 400 to 1000 mg per day, most preferably in the range of 700 to 800 mg per day.
  • the very high-dose oral formulations described hereinbefore are the preferred presentations for administrati ..
  • a suitable daily dose for use in prophylaxis will generally be in the range of 0.1 mg to 50 mg.
  • the desired dose may conveniendy be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the compound is conveniently administered in unit dosage form.
  • the compound 2-fluoro-7-(3-pyridinylmethyl)-9Ii-carbazole monohydrochloride is preferably administered to human patients in two or more subdoses per day so as to obtain constantly effective, non-toxic plasm levels.
  • the molar ratio of active ingredient : cyclodextrin can range from 1 : 1 to 1 : 100, preferably from 1:5 to 1:25 and in particular from 1:8 to 1:13.
  • compositions of 2-fluoro-7-(3-pyridinylmethyl)-9H-carbazole monohydrochloride with cyclodextrin ranges from 2: 1 to 1 : 10 and in particular from 1:1 to 1:3.
  • compositions of the present invention may also be used in combination with other therapeutic agents, for example, other androgen and/or oestrogen lowering agents, or anticancer agents.
  • compositions of the invention may be employed together with known anticancer agents.
  • the invention thus provides, in a further aspect, a combination comprising a composition as defined herein, together with another therapeutically active agent in particular an anticancer agent.
  • compositions of compounds of formula (I) When compositions of compounds of formula (I) are used in combination with a second therapeutic agent, the compositions may be administered either sequentially or simultaneously by any of the routes described above.
  • Suitable therapeutic agents for use in the combinations defined above include, for example cyproterone acetate, flutamide and nilutamide (Anandron®).
  • each compound When compounds of formula (I) are used in combination with a second therapeutic agent effective to reduce levels of androgens and/or oestrogens in a mammal including a human, the dose of each compound may vary from that when the compound is used alone. Thus when compounds of formula (I) are used together with a second therapeutic agent the dose of each compound may be the same or different to that employed when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • Example 1 Solubility test results in function of pH and amount of solubilizing agent.
  • Several stock solutions of 2-hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) in distilled water were prepared and brought to the required pH using a phosphate / citrate buffer.
  • the concentrations of cyclodextrin ranged from 2.5% to 10% (w/v), the pH values from about 2 to about 4.
  • solubility data (mg/ml) are summarized in the table below. K s values were calculated from the solubility data.
  • the solution did not deteriorate in any respect after 1 week storage at 60°C or 1 week storage in a light cabinet (17000 lux).
  • a low-dosage formulation with 1 g of the active ingredient and 50 g HP- ⁇ -CD was prepared in the same manner and had similar physicochemical characterics.
  • Another high-dosage formulation with 5 g of the active ingredient and 300 g HP- ⁇ -CD was prepared following the above method and also had positive stability characteristics.
  • a fourth formulation with 400 g HP- ⁇ -CD and 20 g of the active ingredient was prepared following similarly. The resulting solution had appropriate physicochemical characteristics.
  • Example 6 Solubility test results in function of co- solvent.
  • solvent solubihty propylene glycol > 50 (mg/g) glycerine 45.8 (mg g) ethanol > 50 (mg/g) polyethylene glycol 400 (PEG 400) > 50 (mg g) acetone 1 (mg ml)
  • Example 7 Oral formulations of Compound 2.

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Abstract

Cette invention se rapporte à des compositions pharmaceutiques comprenant des dérivés de carbazole de la formule (I) dans laquelle R1 et R4 représentent chacun, indépendamment, un atome d'hydrogène ou un groupe alkyle en C1-6; chaque R2 peut être identique ou différent et représente un groupe d'enlèvement d'électrons; chaque R3 peut être identique ou différent et représente un groupe d'enlèvement d'électrons; R5 représente un groupe de la formule (a), (b) ou (c); R6 représente un atome d'halogène, un groupe alkyle en C1-6; m vaut zéro ou un nombre entier de 1 à 4; n vaut zéro ou un nombre entier de 1 à 3; et p vaut zéro, 1 ou 2. L'invention se rapporte également aux sels pharmaceutiquement acceptables et aux solvates de ces dérivés, ainsi qu'aux cyclodextrines, et aux procédés de préparation de ces compositions, et à leur utilisation dans la fabrication de médicaments qui réduisent les taux d'androgène et/ou d'÷strogènes chez les mammifères, y compris chez l'homme.
PCT/EP1995/004295 1994-11-07 1995-10-31 Compositions comprenant des carbazoles et des cyclodextrines WO1996014090A1 (fr)

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AU38463/95A AU3846395A (en) 1994-11-07 1995-10-31 Compositions comprising carbazoles and cyclodextrins

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EP94203242 1994-11-07

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6194181B1 (en) 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
WO2002046186A1 (fr) 2000-12-08 2002-06-13 Takeda Chemical Industries, Ltd. Dérivés thiazole substitués porteurs de groupes 3-pyridyl, procédé d'élaboration et leur utilisation
US6683100B2 (en) 1999-01-19 2004-01-27 Novartis Ag Organic compounds
US6776164B2 (en) 1998-06-05 2004-08-17 Interag Enhanced intravaginal devices
US6960586B2 (en) 2000-11-20 2005-11-01 Takeda Pharmaceutical Company Limited Imidazole derivatives, process for their preparation and their use
EP1681290A2 (fr) 2000-11-17 2006-07-19 Takeda Pharmaceutical Company Limited Dérivés d'imidazole, leur procédé de préparation et leur application pharmaceutique
WO2010149755A1 (fr) 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
WO2012035078A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Inhibiteurs de la 17α-hydroxylase/c17,20-lyase
WO2012149413A1 (fr) 2011-04-28 2012-11-01 Novartis Ag Inhibiteurs de 17α-hydroxylase/c17,20-lyase
JP2013508417A (ja) * 2009-10-23 2013-03-07 ヘルス リサーチ インコーポレイテッド アンドロゲン受容体陽性癌を処置する方法
WO2014158875A1 (fr) 2013-03-14 2014-10-02 Pellficure Pharmaceuticals Inc. Nouvelle thérapie pour le carcinome de la prostate
US9655868B2 (en) 2010-08-04 2017-05-23 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
WO2018080933A1 (fr) 2016-10-24 2018-05-03 Pellficure Pharmaceuticals Inc. Compositions pharmaceutiques de 5-hydroxy-2-méthylnaphtalène-1, 4-dione
US10093620B2 (en) 2014-09-12 2018-10-09 Pellficure Pharmaceuticals, Inc. Compositions and methods for treatment of prostate carcinoma

Citations (1)

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WO1994027989A1 (fr) * 1993-05-21 1994-12-08 Glaxo Group Limited Derives de carbazole a activite d'inhibition de 17,20-lyase

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WO1994027989A1 (fr) * 1993-05-21 1994-12-08 Glaxo Group Limited Derives de carbazole a activite d'inhibition de 17,20-lyase

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CESK. FARM. (1993), 42(4), 181-3 CODEN: CKFRAY;ISSN: 0009-0530 *
DATABASE CHEMABS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KRALOVA, K. ET AL: "Effect of interactions with.beta.- cyclodextrin on the solubility of anthracene and some trinuclear heterocyclic compounds in aqueous solutions" *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6194181B1 (en) 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US6380227B1 (en) 1998-02-19 2002-04-30 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US6656711B2 (en) 1998-02-19 2003-12-02 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US7101702B2 (en) 1998-02-19 2006-09-05 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US6776164B2 (en) 1998-06-05 2004-08-17 Interag Enhanced intravaginal devices
US6683100B2 (en) 1999-01-19 2004-01-27 Novartis Ag Organic compounds
EP1681290A2 (fr) 2000-11-17 2006-07-19 Takeda Pharmaceutical Company Limited Dérivés d'imidazole, leur procédé de préparation et leur application pharmaceutique
US7141598B2 (en) 2000-11-17 2006-11-28 Takeda Pharmaceutical Company, Ltd. Imidazole derivatives, production method thereof and use thereof
US6960586B2 (en) 2000-11-20 2005-11-01 Takeda Pharmaceutical Company Limited Imidazole derivatives, process for their preparation and their use
WO2002046186A1 (fr) 2000-12-08 2002-06-13 Takeda Chemical Industries, Ltd. Dérivés thiazole substitués porteurs de groupes 3-pyridyl, procédé d'élaboration et leur utilisation
WO2010149755A1 (fr) 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
JP2013508417A (ja) * 2009-10-23 2013-03-07 ヘルス リサーチ インコーポレイテッド アンドロゲン受容体陽性癌を処置する方法
EP2490531A4 (fr) * 2009-10-23 2013-06-19 Panacela Labs Inc Méthode pour le traitement de cancers positifs aux récepteurs des androgènes
US8835447B2 (en) 2009-10-23 2014-09-16 Health Research Inc. Method for treating androgen receptor positive cancers
US9655868B2 (en) 2010-08-04 2017-05-23 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
US9877932B2 (en) 2010-08-04 2018-01-30 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
US10245240B2 (en) 2010-08-04 2019-04-02 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
WO2012035078A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Inhibiteurs de la 17α-hydroxylase/c17,20-lyase
WO2012149413A1 (fr) 2011-04-28 2012-11-01 Novartis Ag Inhibiteurs de 17α-hydroxylase/c17,20-lyase
WO2014158875A1 (fr) 2013-03-14 2014-10-02 Pellficure Pharmaceuticals Inc. Nouvelle thérapie pour le carcinome de la prostate
US10093620B2 (en) 2014-09-12 2018-10-09 Pellficure Pharmaceuticals, Inc. Compositions and methods for treatment of prostate carcinoma
US10577315B2 (en) 2014-09-12 2020-03-03 Pellficure Pharmaceuticals, Inc. Compositions and methods for treatment of prostate carcinoma
WO2018080933A1 (fr) 2016-10-24 2018-05-03 Pellficure Pharmaceuticals Inc. Compositions pharmaceutiques de 5-hydroxy-2-méthylnaphtalène-1, 4-dione

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TR199501376A2 (tr) 1996-06-21
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ZA959388B (en) 1997-05-06

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