WO2015134670A1 - Dérivés deutérés du ganaxolone - Google Patents

Dérivés deutérés du ganaxolone Download PDF

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Publication number
WO2015134670A1
WO2015134670A1 PCT/US2015/018827 US2015018827W WO2015134670A1 WO 2015134670 A1 WO2015134670 A1 WO 2015134670A1 US 2015018827 W US2015018827 W US 2015018827W WO 2015134670 A1 WO2015134670 A1 WO 2015134670A1
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compound
deuterium
atom
replaced
solvate
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PCT/US2015/018827
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English (en)
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Mingbao Zhang
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Mingbao Zhang
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • isotopologues of ganaxolone which are effective in modulating the GAB A receptor chloride ionophore complex (GR complex) in vitro and exhibit useful therapeutic effects in animal models of human central nervous system (CNS) disorders.
  • Isotoplogues are molecules that only differ in their isotopic compositions.
  • Ganaxolone or 3 ⁇ -hydroxy-3 ⁇ -methyl-5 ⁇ -pregnan-20-one (Compound 1)
  • PTSD posttraumatic stress disorder
  • Compound 1 is being investigated in clinical trials as a therapy for epilepsy and posttraumatic stress disorder (PTSD) and may be useful to treat other CNS disorders (Hogenkamp, D. J. et al /. Med. Chem. 1997, 40, 61-72.)
  • Compound 1 is rapidly absorbed and extensively metabolized by P450 liver enzymes (Monaghan, E. P., et al, Epilepsia 1997, 38, 1026-1031. Nohria, V., et al Neurotherapeutics 2007, 4, 102-105.) after oral administration. Because of its high first pass metabolism, compound 1 must be dosed in high amount to achieve therapeutically adequate systemic exposure by saturating the liver enzymes. Therapeutic agents that must be dosed at high amount are generally less desirable because of poor patient compliance, high cost of goods and potentially high toxicity. Thus, there remains a need for analogues of compound 1 that retain the pharmacological properties of 1 with improved metabolic profiles.
  • Isotoplogues are molecules whose structures differ only in their isotopic
  • compositions are expected to have similar biochemical potency and selectivity as the shape and size of the isotopes are very similar.
  • ADME absorption, distribution, metabolism, and/or excretion
  • replacing one or more hydrogen atoms at certain positions of a drug molecule with deuterium atoms can affect its metabolism mediated by oxidative liver enzymes as exemplified by US patents 8450492, 8461197, 8471034, and others.
  • the same patents also disclose that the effects of such deuterium replacements on drug metabolism are generally unpredictable. Deuterated versions of a subject drug molecule must be synthesized and tested before one can definitively know the effects of isotope replacement if there is any.
  • the invention in one aspect, relates to novel isotoplogues of 3a- hydroxy-3 -methyl-5a-pregnan-20-one (ganaxolone, compound 1), and pharmaceutical compositions comprising an isotopologue of compound 1 and a carrier, excipient, or diluent.
  • Methods of treating or preventing CNS disorders using pharmaceutical compositions containing isotoplogues of compound 1 are also provided.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are hydrogen or deuterium; provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is deuterium; or an ester, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.
  • the isotopologue compounds disclosed are effective in modulating the GABA receptor chloride ionophore complex (GR complex) in vitro, exhibit useful therapeutic effects in animal models of human central nervous system (CNS) disorders which are predictive of their utility as therapeutic agents for the treatment of a variety central nervous system disorders.
  • GR complex GABA receptor chloride ionophore complex
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are as described above.
  • a pharmaceutical composition comprising a compound of Formula (I) or (II).
  • the pharmaceutical composition can be in the form of submicron particles, said particles being suspended in an aqueous or nonaqueous liquid, or forming a complex with cyclodextrin.
  • the pharmaceutical composition can be in the form of an inclusion complex with cyclodextrin.
  • the pharmaceutical composition can be in the form of submicron/nano particles stabilized with a stabilizer selected from hydroxypropyl methyl cellulose (HPMC), sodium lauryl sulfate, and polyvinyl alcohol.
  • HPMC hydroxypropyl methyl cellulose
  • sodium lauryl sulfate sodium lauryl sulfate
  • polyvinyl alcohol polyvinyl alcohol
  • Formula (I) or Formula (I) to treat a central nervous system (CNS) disorder are included in Formula (I) or Formula (I) to treat a central nervous system (CNS) disorder.
  • central nervous system disorder is selected from posttraumatic stress disorder (PTSD), Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Niemann- Pick Type C, FXTAS and Fragile X Syndrome, Diabetic Neuropathy, epilepsy including Status Epilepticus, and Traumatic Brain Injury.
  • PTSD posttraumatic stress disorder
  • Alzheimer's Disease Alzheimer's Disease
  • Parkinson's Disease Multiple Sclerosis
  • Niemann- Pick Type C Niemann- Pick Type C
  • FXTAS and Fragile X Syndrome Diabetic Neuropathy
  • epilepsy including Status Epilepticus
  • Traumatic Brain Injury Traumatic Brain Injury
  • a method of prophylaxis or treatment of a central nervous system disorder comprising administering to a patient in need of such treatment an effective dose of a compound of Formula (I)
  • central nervous system disorder is selected from posttraumatic stress disorder (PTSD), Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Niemann-Pick Type C, FXTAS and Fragile X Syndrome, Diabetic Neuropathy, epilepsy including Status Epilepticus, and Traumatic Brain Injury.
  • PTSD posttraumatic stress disorder
  • Alzheimer's Disease Alzheimer's Disease
  • Parkinson's Disease Multiple Sclerosis
  • Niemann-Pick Type C Niemann-Pick Type C
  • FXTAS and Fragile X Syndrome Diabetic Neuropathy
  • epilepsy including Status Epilepticus
  • Traumatic Brain Injury Traumatic Brain Injury
  • a method of prophylaxis or treatment of a central nervous system disorder comprising administering to a patient in need of such treatment an effective dose of a compound of Formula (II).
  • central nervous system disorder is selected from posttraumatic stress disorder (PTSD), Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Niemann-Pick Type C, FXTAS and Fragile X Syndrome, Diabetic Neuropathy, epilepsy including Status Epilepticus, and Traumatic Brain Injury.
  • PTSD posttraumatic stress disorder
  • Alzheimer's Disease Alzheimer's Disease
  • Parkinson's Disease Multiple Sclerosis
  • Niemann-Pick Type C Niemann-Pick Type C
  • FXTAS and Fragile X Syndrome Diabetic Neuropathy
  • epilepsy including Status Epilepticus
  • Traumatic Brain Injury Traumatic Brain Injury
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention (see, e.g., Berge et al., J. Pharm. Sci. 1977, 66, 1-19.).
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species, farm animals such as cattle, horses, sheep, goats, swine, domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs and the like.
  • non- mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, reliving a condition caused by the disease or condition or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • pharmaceutically effective amount refers to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease.
  • An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), pulmonary, nasal, topical and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion
  • pulmonary nasal, topical and rectal administration.
  • Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein, e.g., as discussed in Goodman and Oilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton Pa.
  • tautomer refers to all isomeric forms of the compound which may exist alone or in equilibrium with each other in solution due to the presence of a tautomeric group or groups in a molecule. Such isomerization is called tautomerization and is the formal migration of a hydrogen atom within a molecule, accompanied by a switch of a single bond and an adjacent double bond. Groups which are tautomeric pairs include, but are not limited to, keto-enol, imine-enamine, lactam-lactim and amide-imidic acid.
  • isotopic enrichment factor refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. Thus, a preparation of ganaxolone will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as ⁇ " or “hydrogen”
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • a position is designated specifically as “D” or “deuterium”
  • the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium which is about 0.015% (i.e., at least 50.1% incorporation of deuterium).
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • a compound represented by a particular chemical structure containing indicated deuterium atoms will also contain lesser amounts of isotoplogues having hydrogen atoms at one or more of the designated deuterium positions in that structure.
  • the relative amount of such isotopologues in a compound of this invention will depend on a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthetic steps used to prepare the compound.
  • the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.
  • the compound of Formula (I) may contain additional asymmetric carbon centers due to deuterium substitution.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration.
  • Preferred isomers are those with the absolute configuration which produces the compound of Formula (I) with the more desirable biological activity.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two aromatic rings of the specified compounds.
  • R 5 are deuterium and R 1 -R 3 , and R 6 -R 11 are hydrogen is illustrated below in Reaction Scheme 1.
  • ganaxolone 1 which can be prepared according to literature methods (Hogenkamp, D. J. et al /. Med. Chem. 1997, 40, 61-72), is brominated with, for example, NBS, to form an intermediate of structure 2, which in the presence of a strong base such as DBU undergoes an elimination reaction to form the compound of structure 3.
  • a strong base such as DBU undergoes an elimination reaction to form the compound of structure 3.
  • Catalytic hydrogenation of 3 using deuterium gas ( 2 H 2 ) provides the compound of structure 4.
  • the compound of structure 4 is subjected to treatment with a strong base such as sodium methoxide, in an appropriate protic solvent, such as methanol, to produce the compound of structure 5.
  • a strong base such as sodium methoxide
  • an appropriate protic solvent such as methanol
  • the compound of structure 4 is allowed to react with a halogenating agent such as NBS, to give the compound 6.
  • a halogenating agent such as NBS
  • Dehydrohalogenation of 6 with a base, such as DBU provides the enone of structure 7; catalytic hydrogenation using deuterium gas gives the trideuterated product 8, which can be converted to the compound of structure 9 containing two deuterium atoms attaching to the C-16.
  • 5 ⁇ -pregnen-3 ⁇ -ol-20-one acetate 10 which can be obtained from tigogenin or tigogenin acetate as described in US patent 2885411, is allowed to undergo catalytic hydrogenation using deuterium gas ( 2 H 2 ), to provide the trideuterated compound of structure 11.
  • Hydrolysis of 11 under basic conditions suitable for cleaving an acetoxy group such as potassium carbonate in methanol provides the hydroxy compound of structure 12, which is oxidized by using an oxidant suitable for oxidizing a secondary alcohol to a ketone such as Dess-Martin periodinane in dichloromethane to the corresponding 3,20-dione 13.
  • Sensitive or reactive groups on any of the intermediate compounds may need to be protected and deprotected during any of the above methods for forming esters.
  • Protecting groups in general may be added and removed by conventional methods well known in the art (see, e.g., T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, 1999).
  • the pharmaceutical compositions comprise an effective amount of a compound of Formulae (I)-(II), or an ester, a pharmaceutically acceptable salt, solvate, hydrate or derivative thereof. In some embodiments, the pharmaceutical compositions comprise an effective amount of a compound of Formulae (I)-(II) and at least one pharmaceutically acceptable carrier. In some embodiments the pharmaceutical compositions are for the treatment of central nervous system disorders. In some embodiments, the pharmaceutical compositions are for the treatment of central nervous system disorders in a mammal.
  • Ganaxolone (Compound 1) is prepared according to literature methods, e.g.,
  • Celite® diatomaceous earth trademark of Celite Corporation
  • the 16 ⁇ - 2 H, 17 ⁇ - 2 H ganaxolone (4) (267 mg) is treated with N- bromosuccinimide (353 mg) in CC1 4 (12 mL) in the presence of benzoyl peroxide (2 mg) to obtain the 17-bromo ganaxolone intermediate 6.
  • Treatment of 6 with 1,8-diazabicyclo[5,4,0]-undec-7-ene (0.83 mL) in refluxing toluene (13 mL) affords the enone 7 after flash hromatography (180 mg).
  • Catalytic hydrogenation of 7 with deuterium gas (Pd/C, ethyl acetate) affords the ganaxolone- 2 H3 compound 8.
  • Stock solutions (1.2 mM) of test compounds are prepared in acetonitrile.
  • the stock solutions are diluted to 0.12 mM in acetonitrile (ACN).
  • the 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 2 mM MgCl 2 .
  • the diluted microsomes (1.5 mL) are added to glass tubes saturated with 0.12 ⁇ test compound in triplicate. 2 ⁇ of the 0.12 mM test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of 498 ⁇ L of pre- warmed 2 mM NADPH solution.
  • the final reaction volume is 2 mL and contains 0.469 mg/mL human liver microsomes, and 0.12 ⁇ of test compound.
  • the reaction mixtures are incubated at 37 °C for 0, 5, 10, 20, and 30 minutes.
  • 200 ⁇ L aliquots are removed and mixed with 200 ⁇ L of acetonitrile containing internal standard to stop the reaction.
  • the samples are centrifuged at 3000 rpm for 10 minutes. The supernatant is transferred to a clean HPLC vial for LC/MS/MS analysis.
  • the percent parent remaining is determined by comparing the concentration of test compound at each time point to the concentration at time zero (100%). The calculation results are presented in an Excel spreadsheet (Microsoft® Excel).
  • Compounds of Formula (I) or (II) can be used in the treatment of central nervous system disorders, as evidenced by their activity in animal models of human central nervous system (CNS) disorders.
  • CNS central nervous system
  • disorders include, but are not limited to, posttraumatic stress disorder (PTSD), Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Niemann- Pick Type C, FXTAS and Fragile X Syndrome, Diabetic Neuropathy, epilepsy including Status Epilepticus, and Traumatic Brain Injury.
  • compositions described herein may be administered, to a patient in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the methods comprise administering an effective amount of a compound of Formulae (I)-(II), or a pharmaceutically acceptable salt, ester, solvate, hydrate or derivative thereof, alone or in combination with an amount of a second chemo therapeutic.
  • a chemotherapeutic When used in combination with a chemotherapeutic, the amounts of the compound, ester, salt, solvate, hydrate or derivative, and of the chemotherapeutic are together effective in epilepsy and posttraumatic stress disorder (PTSD) and may be useful to treat other CNS disorders.
  • chemotherapeutics include for example, conventional antiepileptic drugs (CAEDs) and positive allosteric modulator of GABA A receptors.
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), pulmonary, nasal, topical, and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion
  • pulmonary including nasal, topical, and rectal administration.
  • compounds described herein can be administered locally to the area in need of treatment.
  • This may be achieved by, for example, but not limited to, local infusion during surgery, topical application, e.g., cream, ointment, injection, catheter, or implant, said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • topical application e.g., cream, ointment, injection, catheter, or implant
  • said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • the administration can also be made by direct injection at the site (or former site) of a tumor or neoplastic or pre-neoplastic tissue.
  • compositions and methods described herein may also be used in conjunction with other well-known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the compositions described herein and, in embodiments where combinational therapy is employed other agents do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes.
  • the determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition is well within the knowledge of the skilled clinician.
  • the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • the particular choice of compounds used will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
  • the compounds may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the CNS disease, the condition of the patient, and the actual choice of compounds used.
  • the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.
  • the compound of Formulae (I)-(II), or a pharmaceutically acceptable salt, ester, solvate, hydrate or derivative thereof is administered with at least one other anti-convulsant agent.
  • the compound of Formulae (I)-(II), or a pharmaceutically acceptable salt, ester, solvate, hydrate or derivative thereof is administered with at least one other anti-epileptic agent.
  • the compound of Formulae (I)-(II), or a pharmaceutically acceptable salt, ester, solvate, hydrate or derivative thereof is administered with at least one other anti- anxiety agent.
  • the ganaxolone formulation is administered with at least one other anti-depression agent.
  • the methods comprise administering an effective amount of a compound of Formulae (I)-(II), or a pharmaceutically acceptable salt, ester, solvate, hydrate or derivative thereof, in combination with maximal electroshock (MES) induced and Pentylenetetrazol (PTZ) induced convulsions.
  • MES maximal electroshock
  • PTZ Pentylenetetrazol
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intra peritoneal, transmucosal, transdermal, rectal, pulmonary, nasal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, or solvate, hydrate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
  • active ingredient active ingredient
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion or submicron particles suspended in aqueous or non- aqueous liquid or complexes with cyclodextrins.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, nanoparticle suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, solubilizing and/or dispersing agents.
  • the formulations may be presented in unit- dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous
  • sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions may also be formulated as a depot preparation. 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.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth. [0085] Pharmaceutical preparations may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • compositions may be administered topically, that is by non- systemic administration.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch, or large porous particles in which the active drug molecules are embedded as stabilized nanoparticles.
  • a powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds or compositions described herein can be delivered in a vesicle, e.g., a liposome (see, for example, Langer, Science 1990, 249, 1527-1533; Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein, Fidler and foremost, Ed., Liss, N.Y., pp. 353-365, 1989).
  • the compounds and pharmaceutical compositions described herein can also be delivered in a controlled release system.
  • a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 1987,14,201; Buchwald et al. Surgery, 1980, 88, 507; Saudek et al. N. Engl. J. Med. 1989, 321, 574.
  • a controlled release system can be placed in proximity of the therapeutic target. (See, Goodson, Medical Applications of Controlled Release, 1984, Vol. 2, pp. 115-138).
  • compositions described herein can also contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl- pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl- cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethylene glycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • compositions may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • a solubilizing agent such as a cyclodextrin may be included in the pharmaceutical composition.
  • the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
  • the injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the sterile injectable preparation may also be a sterile injectable nanoparticle suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a nanoparticle suspension in sterile water.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug substance with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • creams, ointments, jellies, solutions or suspensions, etc., containing a compound or composition of the invention can be used.
  • topical application can include mouth washes and gargles.
  • compositions may be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regiment.
  • Pharmaceutical compositions may contain the active ingredient in the form of submicron/nano particles stabilized with various stabilizers such hydroxypropyl methyl cellulose (HPMC), sodium lauryl sulfate, polyvinyl alcohol.
  • Pharmaceutical compositions may contain the active ingredient in the form of inclusion complexes with cyclodextrins.
  • the amount of pharmaceutical compositions administered will firstly be dependent on the mammal being treated.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, sex, diet, weight, general health and response of the individual patient, the severity of the patient's symptoms, the precise indication or condition being treated, the severity of the indication or condition being treated, time of administration, route of administration, the disposition of the composition, rate of excretion, drug combination, and the discretion of the prescribing physician.
  • the route of administration may vary depending on the condition and its severity.
  • the pharmaceutical composition is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The amount and frequency of administration of the compounds described herein, and if applicable other therapeutic agents and/or therapies, will be regulated according to the judgment of the attending clinician (physician) considering such factors as described above. Thus the amount of pharmaceutical composition to be administered may vary widely.
  • Administration may occur in an amount of between about 0.001 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), more preferably at least about 5 mg/kg of body weight per day.
  • a particular therapeutic dosage can include, e.g., from about 0.01 mg to about 7000 mg of compound, and preferably includes, e.g., from about 0.05 mg to about 3000 mg.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1500 mg, according to the particular application. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
  • active compound may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention a pour objectif de fournir, dans un aspect décrit ci-après, de nouveaux isotopologues de la 3α-hydroxy-3β-méthyl-5α-prégnan-20-one (ganaxolone). Conformément à un aspect de l'invention, un composé isotopologue de formule générale (I) est décrit, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 et R11 étant hydrogène ou deutérium (2H) ; à condition qu'au moins l'un de R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 et R11 est deutérium (2H) ; ou un ester, un hydrate, un solvate, ou un sel pharmaceutiquement acceptable. Les isotopologues selon l'invention sont efficaces pour moduler le complexe ionophore au chlorure/récepteur GABA (complexe GR) in vitro et présentent des effets thérapeutiques utiles sur les troubles du système nerveux central (SNC) de l'homme.
PCT/US2015/018827 2014-03-05 2015-03-04 Dérivés deutérés du ganaxolone WO2015134670A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016164763A1 (fr) * 2015-04-10 2016-10-13 Sage Therapeutics, Inc. Compositions et méthodes permettant de traiter des troubles du snc
WO2024020953A1 (fr) * 2022-07-28 2024-02-01 湖南科益新生物医药有限公司 Composé stéroïde pour traiter une maladie du système nerveux central, son procédé de préparation, son utilisation et composition pharmaceutique associée

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007062266A2 (fr) * 2005-11-28 2007-05-31 Marinus Pharmaceuticals Formes galeniques de ganaxolone et procedes de preparation et d'utilisation de celles-ci
US20110282587A1 (en) * 2010-05-17 2011-11-17 Emory University Computer readable storage mediums, methods and systems for normalizing chemical profiles in biological or medical samples detected by mass spectrometry
US20120316146A1 (en) * 2010-01-21 2012-12-13 Monash University Anaesthetic formulation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007062266A2 (fr) * 2005-11-28 2007-05-31 Marinus Pharmaceuticals Formes galeniques de ganaxolone et procedes de preparation et d'utilisation de celles-ci
US20120316146A1 (en) * 2010-01-21 2012-12-13 Monash University Anaesthetic formulation
US20110282587A1 (en) * 2010-05-17 2011-11-17 Emory University Computer readable storage mediums, methods and systems for normalizing chemical profiles in biological or medical samples detected by mass spectrometry

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016164763A1 (fr) * 2015-04-10 2016-10-13 Sage Therapeutics, Inc. Compositions et méthodes permettant de traiter des troubles du snc
WO2024020953A1 (fr) * 2022-07-28 2024-02-01 湖南科益新生物医药有限公司 Composé stéroïde pour traiter une maladie du système nerveux central, son procédé de préparation, son utilisation et composition pharmaceutique associée

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