WO2010054565A1 - Promédicament hydrosoluble du (r)-(-)-bicalutamide, son procédé de préparation et ses utilisations - Google Patents

Promédicament hydrosoluble du (r)-(-)-bicalutamide, son procédé de préparation et ses utilisations Download PDF

Info

Publication number
WO2010054565A1
WO2010054565A1 PCT/CN2009/073425 CN2009073425W WO2010054565A1 WO 2010054565 A1 WO2010054565 A1 WO 2010054565A1 CN 2009073425 W CN2009073425 W CN 2009073425W WO 2010054565 A1 WO2010054565 A1 WO 2010054565A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
oxo
trifluoromethyl
methyl
bicalutamide
Prior art date
Application number
PCT/CN2009/073425
Other languages
English (en)
Chinese (zh)
Inventor
吕辉
王振雷
陈义朗
车晓明
Original Assignee
上海阳帆医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海阳帆医药科技有限公司 filed Critical 上海阳帆医药科技有限公司
Publication of WO2010054565A1 publication Critical patent/WO2010054565A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl

Definitions

  • This invention relates to the field of pharmacy.
  • the present invention relates to a non-anti-androgen compound, a process for its preparation and use. More specifically, the present invention relates to a novel (R)-(-)-bicalutamide prodrug which is water-soluble and has high oral bioavailability, and a process and use thereof. Background technique
  • a prodrug is a therapeutic agent that is itself inactive but is converted in vivo to a therapeutically active parent molecule.
  • Prodrugs have optimized physicochemical, pharmacokinetic and pharmacodynamic properties. They can be designed to overcome pharmacy, pharmacokinetic or pharmacodynamic defects such as insufficient oral absorption, poor solubility, insufficient chemical stability, difficulty in preparing the drug, and the like.
  • Bicalutamide (Casodex) is a non-androgenic antihormonal drug developed by AstraZeneca [US Patent 4,636,505]. Bicalutamide is marketed as a racemate and is used clinically for the treatment of prostate cancer, benign prostatic hyperplasia and other diseases.
  • Bicalutamide can be split into two isomers, (R)-(-)-bicalutamide and (S)-(+)-bicalutamide, the biological activity of which is derived from (R)- ( -) -Bicalutamide, (S)-(+)-Bicalutamide has almost no antiandrogenic activity and is ineffective.
  • the one-enantiomer stereo configuration of bicalutamide does not shift, but its metabolic properties show great stereoselectivity [Xenobiotica, 1995, 25 (6), 623-635] .
  • the above two isomers are metabolized in the liver, and the rate of metabolism and elimination of the inactive (s)-(+)-bicalutamide (R) _ (-) - bicalutamide is much faster, therefore, the (S)-isomer can put a lot of pressure on the liver, especially those with impaired liver function [Tetrahedron, 2002, 58, 5905 -5908].
  • the object of the present invention is to provide a novel (R)-(-)-bicalutamide prodrug which has good water solubility and high oral bioavailability.
  • Another object of the present invention is to provide a process and use of the prodrug.
  • M may be an alkali metal, an alkaline earth metal or an organic amine alcohol cation
  • it is WI® or ⁇ 2 ®
  • the ⁇ ® is sodium or potassium; it is a calcium ion, or a magnesium ion.
  • the ⁇ ® is sodium or potassium; it is a calcium ion, or a magnesium ion.
  • the compound is selected from the group consisting of:
  • Compound (1)-2 (s)-[1-oxo- 1 -(3-trifluoromethyl-4-cyanoanilino)-2-methyl-3-(4-fluorophenylsulfonyl) ]-2-propoxymethyl phosphate disodium salt;
  • Compound (1)-3 (s)- [1-oxo- 1 - (3-trifluoromethyl-4-cyanoanilinyl) -2-methyl-3-(4-fluorophenylsulfonyl)]-2-propoxymethyl phosphate diglucosamine salt;
  • Compound (1)-4 (s)-[1-oxo- 1 -(3-trifluoromethyl-4-cyanoanilino)-2-methyl-3-(4-fluorophenylsulfonyl) ]-2-propoxymethyl phosphate diethanolamine salt;
  • Compound (1)-5 (s)-[1-oxo- 1 -(3-trifluoromethyl-4-cyanoanilino)-2-methyl-3-(4-fluorophenylsulfonyl) ]-2-propyl phosphate; or
  • Compound (1)-6 (s)-[1-oxo- 1 -(3-trifluoromethyl-4-cyanoanilino)-2-methyl-3-(4-fluorophenylsulfonyl) ]-2-propyl phosphate disodium salt.
  • compound 1 in an inert solvent, compound 1 is reacted with iodosuccinimide (NIS) and di-tert-butyl phosphate to form compound 2;
  • NIS iodosuccinimide
  • compound 2 is reacted with trifluoroacetic acid to form compound (i)-i;
  • step (c) further comprises: reacting the compound (1)-1 with a base in an inert solvent to form a compound (la)
  • compound 4 in an inert solvent, compound 4 is oxidized with m-chloroperoxybenzoic acid to form compound 5;
  • step (c) further comprises: reacting compound (I)-5 with a base in an inert solvent to form compound (lb)
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of the first aspects of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, Hydrate or solvate.
  • the mammal is a human.
  • a method of treating a disease comprising the steps of: administering a compound of formula (I) of the invention, or a crystalline form, a pharmaceutically acceptable salt, a hydrate thereof, or a subject to a subject in need thereof Solvate.
  • the disease is a prostate tumor or an androgen related disease in a male mammal. More preferably, the mammal is a human.
  • the inventors have extensively and intensively studied, screened and studied a large number of compounds, and found for the first time that the compound represented by the above formula (I) has not only good water solubility but also good oral bioavailability. Whether the compound of the above formula (I) is administered orally or by injection, the (R)-(-)-bicalutamide can be rapidly and quantitatively released in the animal, and its oral bioavailability (84.5%) and ratio are Karruamide (45. 1%) increased by nearly 40%. Therefore, the above compound of the formula (I) overcomes the disadvantages of poor water solubility and low oral bioavailability of bicalutamide, and is particularly suitable for the treatment of male or human prostate tumors and androgen-related diseases. The inventors have completed the present invention on this basis. Active ingredient
  • the term "compound of the invention” refers to a compound of formula (I).
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the present invention which is formed with an acid or a base and which is suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, pic
  • a preferred class of salts are salts of the compound of the present invention and a base.
  • Bases suitable for salt formation include, but are not limited to, alkali metal hydroxides, alkaline earth metal hydroxides, amines, amine alcohols (e.g., C1-C6 amine alcohols), various sugar amines.
  • Preferred inorganic bases include sodium hydroxide, sodium hydrogencarbonate, sodium carbonate; preferred organic bases include ethanolamine, D-glucosamine.
  • alkyl includes straight-chain or branched alkyl groups, and also includes cycloalkyl groups.
  • Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl, pentyl, hexyl, and the like. Representative compounds of the invention are shown in Table 1.
  • the preparation method of the structural compound of the formula (I) of the present invention is more specifically described below, but these specific methods do not constitute any limitation on the present invention.
  • the reaction conditions such as the reactants, the solvent, the base, the amount of the compound used, the reaction temperature, and the reaction The required time and the like are not limited to the following explanations.
  • the compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
  • each reaction is usually carried out in an inert solvent at -io °c to reflux temperature (e.g. -10)
  • reaction time is usually from 0.1 to 120 hours, preferably from 0.5 to 80 hours.
  • the compound of formula (I) of the present invention can be prepared as follows:
  • M ⁇ represents a metal cation or an organic amine cation
  • (R) - (-) - Bicalutamide can be prepared by a conventional method [Tetrahedron, 2002, 58, 5905-5908; Chinese Journal of Pharmaceutical Industry, 2006, 37 (2), 73-74].
  • the reaction temperature is not particularly limited and is usually from -10 ° C to the reflux temperature of the solvent, preferably from 0 to 60 V, more preferably from 5 to 5 CTC (e.g., room temperature).
  • the reaction time is not particularly limited and is usually from 1 hour to 5 days, preferably from 3 hours to 4 days. More preferably 12 hours to 3 days.
  • Compound 1 is reacted with iodosuccinimide (NIS) and di-tert-butyl phosphate in an inert solvent to form compound 2.
  • inert solvents suitable for the above reactions include, but are not limited to, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform, and preferred inert solvents include tetrahydrofuran or dichloromethane.
  • the reaction temperature is not particularly limited and is usually from -10 ° C to the reflux temperature of the solvent, preferably from 0 to 60 V, more preferably from 5 to 5 CTC (e.g., room temperature).
  • the reaction time is not particularly limited and is usually from 1 to 72 hours, preferably from 2 to 5 hours.
  • compound 2 in an inert solvent, compound 2 is reacted with trifluoroacetic acid to form compound (1)-1.
  • inert solvents suitable for the above reactions include, but are not limited to, dichloromethane, chloroform; tetrahydrofuran, dioxane.
  • the reaction temperature is not particularly limited and is usually from -10 ° C to the reflux temperature of the solvent, and the preferred temperature is from 0 to 60.
  • reaction time is not particularly limited and is usually from 0.5 to 10 hours, preferably from 1 to 5 hours.
  • Suitable inert solvents include, but are not limited to, ethanol, methanol or water, or a mixture of alcohol and water in any proportion.
  • a preferred solvent is a mixed solvent of ethanol and water (the mixing ratio of the two is usually 20:1 to 1:20; more preferably 10:1 to 1:10).
  • Bases suitable for the above reaction include inorganic bases and organic bases.
  • the inorganic base is preferably sodium hydroxide, sodium hydrogencarbonate or sodium carbonate; the organic base is preferably ethanolamine, D-glucosamine.
  • the reaction temperature is not particularly limited and is usually from -10 ° C to the reflux temperature of the solvent, and the preferred temperature is from 0 to 60.
  • reaction time is not particularly limited and is usually from 0.5 to 10 hours, preferably from 1 to 5 hours.
  • the compound of formula (I) of the present invention can also be prepared as follows:
  • M represents a metal cation or an organic amine cation
  • Compound 3 is commercially available or can be prepared according to the literature method [Chinese Journal of Pharmaceutical Industry 37: 73].
  • Inert solvents suitable for the above reactions include, but are not limited to, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dichloromethane, chloroform or combinations thereof.
  • Preferred inert solvents include tetrahydrofuran or dimethylformamide.
  • Suitable acid binding agents include alkali or a salt, and may be an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate, or an organic base such as triethylamine, pyridine or diisopropylethylamine.
  • Sodium hydroxide is preferred.
  • the reaction temperature is not particularly limited and is usually from -10 ° C to the reflux temperature of the solvent, preferably from 0 to 60 V, more preferably from 5 to 10 ° C.
  • the reaction time is not particularly limited and is usually from 5 to 48 hours, preferably from 10 to 24 hours.
  • Compound 4 is oxidized with m-chloroperoxybenzoic acid in an inert solvent to form compound 5.
  • inert solvents suitable for the above reactions include, but are not limited to, dimethylformamide, dichloromethane, chloroform, toluene, or combinations thereof.
  • the reaction temperature is not particularly limited and is usually -10 ° C to the reflux temperature of the solvent, preferably 0 to 60 ° C, more preferably 15 to 3 CTC (e.g., room temperature).
  • the reaction time is not particularly limited and is usually from 1 to 10 hours, preferably from 2 to 5 hours.
  • Trimethylhalosilanes suitable for the above reactions include, but are not limited to, trimethylbromosilane and trimethyliodosilane, preferably trimethylbromosilane.
  • Suitable inert solvents include, but are not limited to, dichloromethane, chloroform; tetrahydrofuran, dioxane.
  • the reaction temperature is not particularly limited and is usually from -10 ° C to the reflux temperature of the solvent, preferably from 0 to 60 V, more preferably from 5 to 10 ° C.
  • the reaction time is not particularly limited and is usually from 5 to 36 hours, preferably from 10 to 24 hours.
  • Suitable inert solvents include, but are not limited to, ethanol, methanol or water, or a mixture of alcohol and water in any proportion.
  • a preferred solvent is a mixed solvent of ethanol and water (the mixing ratio of the two is usually 20:1 to 1:20; more preferably 10:1 to 1:10).
  • Bases suitable for the above reaction include inorganic bases and organic bases.
  • the inorganic base is preferably sodium hydroxide, sodium hydrogencarbonate or sodium carbonate;
  • the organic base is preferably ethanolamine, D-glucosamine.
  • the reaction temperature is not particularly limited and is usually -10 ° C to the reflux temperature of the solvent, preferably 0-60 V, more preferably 15-3 CTC (e.g., room temperature).
  • reaction time is not particularly limited and is usually from 0.5 to 3 hours, preferably from 1 to 2 hours.
  • Pharmaceutical composition and method of administration is not particularly limited and is usually from 0.5 to 3 hours, preferably from 1 to 2 hours.
  • the compound of the present invention has excellent water solubility and better oral bioavailability
  • the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable salts, hydrates or solvates thereof, and compounds containing the present invention are mainly A pharmaceutical composition of the active ingredient, which can be used to treat prostate tumors in male mammals or to treat androgen related diseases (especially diseases currently treated with bicalutamide).
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains from 1 to 1000 mg of the compound of the invention per agent, more preferably from 10 to 300 mg of the compound of the invention. Usually, one dose is a tablet, a capsule or a vial.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “phase “Capacitive” as used herein means that the components of the composition are capable of blending with the compounds of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carriers are cellulose and Derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as Soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agents (such as sodium lauryl sulfate), coloring Agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and Derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid, magnesium stearate
  • the compound of the present invention when administered, it can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerin; (d) a disintegrant, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetylene glycol
  • Solid dosage forms such as tablets, troches, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric materials and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms of the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is applied to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 1000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the main advantages of the invention include:
  • the drug metabolism property of the compound of the present invention is greatly improved, and has good oral bioavailability.
  • the provided compound has excellent water solubility, and is convenient for making preparation forms with different requirements to meet different drug delivery requirements.
  • Example 1 (s) -2-methyl-2-(methylthiomethoxy)-3-(4-fluorophenylsulfonyl)-N-(4-cyano
  • the compound (I)-1 (1.0 g, 1.9 mmol) was dissolved in water (10 mL), EtOAc (m. %.
  • Tetrahydrofuran (20 mL), IN sodium tetrahydrofuran (20 mL) and Compound 3 (1 ⁇ 8 g, 4.6 mmol) were mixed under an argon atmosphere, and diethyl chlorophosphate (2.7 mL) was added dropwise under ice bath. , 18 ⁇ 8mmol), reacted at room temperature overnight (18 hours), the reaction was stopped, the THF in the system was recovered, and ethyl acetate (50 mL) and water (50 mL) were added to the residue, stirred for 30 minutes, and allowed to stand for separation, organic phase The organic layer was washed with EtOAc (EtOAc m.).
  • the compound of the present invention has good water solubility, is advantageous for preparation of various preparations and obtains better drug metabolism properties, and is convenient for use in various patients, and is very similar to bicalutamide which is hardly soluble in water. Great advantage.
  • Example 12 Pharmacokinetic test of compound (1)-2 in rats
  • Administration by intragastric administration 8 healthy SD rats, male, weighing 200 ⁇ 250 g, were randomly divided into 2 groups, 4 in each group. The doses were 10 mg/kg (11.7 mmol/kg) and 50 mg/kg (85.6 mmol/kg), and the administration volume was 10 ml/kg, which was prepared in physiological saline. Fasting for 12 h before administration, free drinking water, 0.25, 0.5, 1.0, 2.0, 3.0, 5.0, 7.0, 9.0 and 24 h after administration (taken in the high-dose group for 48 h). 0.3 ml of venous blood, placed in heparinized tubes, centrifuged at 3500 rpm for 10 min, plasma was separated, and stored at -20 ° C for testing.
  • Intravenous injection 4 healthy SD rats, male, weighing 200 ⁇ 250 g.
  • the dose was 10 mg/kg (17. lmmol/kg), and the administration volume was 10 ml/kg, which was prepared in physiological saline.
  • Heparinized tubes were centrifuged at 3500 rpm for 10 min, plasma was separated, and stored at -20 ° C for testing.
  • Administration by intragastric administration 8 healthy SD rats, male, weighing 200 ⁇ 250 g, were randomly divided into 2 groups, 4 in each group. The doses were 7.4 mg/kg (17. lmmol/kg) and 36.8 mg/kg (85.6 mmol/kg), respectively, and the administration volume was 10 ml/kg, which was prepared with 0.5% CMC-Na. Fasting for 12 h before administration, free drinking water, 0.25, 0.5, 1.0, 2.0, 3.0, 5.0, 7.0, 9.0 after administration.
  • venous blood was taken from the posterior venous plexus of the rat, placed in heparinized tubes, centrifuged at 3500 rpm for 10 min, and the plasma was separated and stored at -20 °C for testing.
  • Intravenous injection 4 healthy SD rats, male, weighing 200 ⁇ 250 g. The dose was 7.4 mg/kg (17. lmmol/kg), the administration volume was 10 ml/kg, and it was formulated with DMS0, Tween 80 and physiological saline. Fasting for 12 h before administration, free drinking water, venous blood was taken from the posterior venous plexus of rats after 5 min, 15 min, 0.5, 1.0, 2.0, 3.0, 5.0, 7.0, 9.0, 24 and 48 h. Ml, placed in heparinized tubes, centrifuged at 3500 rpm for 10 min, plasma was separated, and stored at -20 ° C for testing.
  • the plasma peak time Tmax of compound (1)-2 and its parent drug (R)-(-)-bicalutamide in plasma was 0.25 and At 6.0 h, the peak concentrations of C max were 0.353 ⁇ 0.240 and 3.30 ⁇ 0.40 g/ml, respectively, and the area under the plasma concentration-time curve was AUC.
  • ⁇ t were 0.187 ⁇ 0.133 and 63.0 ⁇ 12.2 ⁇ ⁇ ⁇ h/ml, respectively, and the plasma elimination half-life t 1/2 was 0.62 ⁇ 0.19 and 27.7 ⁇ 15.6 h, respectively.
  • the plasma peak time Tmax of compound (1)-2 and its parent drug (R)-(-)-bicalutamide in plasma was 0.44 and At 9.0 h, the peak concentration C max was 0.222 ⁇ 0.165 and 17.1 ⁇ 2.5 ⁇ g/ml, respectively, and the area under the plasma concentration-time curve was AUC.
  • - 4 were 0.223 ⁇ 0.127 and 445 ⁇ 59 g - h/ml, respectively, and plasma elimination half-lives t 1/2 were 0.70 ⁇ 0.27 and 14.0 ⁇ 1.3 h, respectively.
  • the plasma peak time Tmax of compound (1)-2 and its parent drug (R)-(-)-bicalutamide in plasma was 0.25.
  • the peak concentrations of C max were 5.72 ⁇ 0.60 and 35.3 ⁇ 8.2 ⁇ g/ml, respectively, and the area under the plasma concentration-time curve was AUC.
  • -1 was 14.1 ⁇ 3.1 and 60.6 ⁇ 3.1 ⁇ ⁇ ⁇ h/ml, respectively.
  • the plasma elimination half-life t 1/2 was 0.75 ⁇ 0.28 and 24.8 ⁇ 3.2 h, respectively.
  • the blood clearance clearance CL was 0.73 ⁇ 0.16 and 0.085 ⁇ 0.006, respectively. LVh/kg.
  • the C max and AUC Q 24 of the parent drug after administration of 50 mg/kg of compound (1)-2 were 5.2 and 5.1 times of the corresponding parameters of the 10 mg/kg dose group, respectively, and were proportional to the dose increase.
  • the plasma peak time T max of bicalutamide in plasma was 5.50 ⁇ 1.00 and 6.50 ⁇ 2.52 h, respectively, and the peak concentration C max was 1.30 ⁇ 0.24 and 2.87 ⁇ 0.38 ⁇ g/ml, area under the plasma concentration-time curve AUC. - 1 was 36.3 ⁇ 7.1 and 76.8 ⁇ 7.5 ⁇ ⁇ ⁇ h/ml, respectively, and the plasma elimination half-life t 1/2 was 24.4 ⁇ 4.8 and 24.2 ⁇ 3.8 h, respectively.
  • Plasma concentration of bicalutamide in plasma after intravenous administration of 7.4 mg/kg bicalutamide Area under the curve AUC. --1 was 80. 4 ⁇ 9. 0 ⁇ ⁇ ⁇ h / ml, the plasma elimination half-life t 1/2 of 21. 1 ⁇ 2. 4 h, all the blood clearance CL to earth 0.076 0. 012 L / h /kg.
  • the plasma exposure of bicalutamide in the high dose (36.8 mg/kg) group was 2.1 times in the low dose group (7.4 mg/kg), and the pharmacokinetic parameters increased less than the dose increase ratio. .
  • the above substances are uniformly mixed, and then filled into ordinary gelatin capsules to obtain 1000 gums.
  • the above substances are uniformly mixed, and then filled into ordinary gelatin capsules to obtain 1000 gums.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur le promédicament hydrosoluble du (R)-(-)-bicalutamide représenté par la formule (I) suivante, sur ses sels pharmaceutiquement acceptables, sur son procédé de préparation et sur ses utilisations. Le composé de formule (I) est utile pour le traitement du cancer de la prostate chez un mâle ou l'homme et de maladies associées à des androgènes.
PCT/CN2009/073425 2008-11-17 2009-08-21 Promédicament hydrosoluble du (r)-(-)-bicalutamide, son procédé de préparation et ses utilisations WO2010054565A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200810202719A CN101735267A (zh) 2008-11-17 2008-11-17 水溶性(r)-(-)-比卡鲁胺前药、其制备方法及用途
CN200810202719.8 2008-11-17

Publications (1)

Publication Number Publication Date
WO2010054565A1 true WO2010054565A1 (fr) 2010-05-20

Family

ID=42169625

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2009/073425 WO2010054565A1 (fr) 2008-11-17 2009-08-21 Promédicament hydrosoluble du (r)-(-)-bicalutamide, son procédé de préparation et ses utilisations

Country Status (2)

Country Link
CN (1) CN101735267A (fr)
WO (1) WO2010054565A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011002184A2 (fr) * 2009-06-30 2011-01-06 Hanmi Pharm. Co., Ltd. Ester d’acide phosphorique de bicalutamide pour traiter le cancer de la prostate

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10927136B2 (en) * 2016-07-07 2021-02-23 Cyclerion Therapeutics, Inc. Phosphorus prodrugs of pyrazolo-substituted pyrimidine sGC stimulators

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037205A2 (fr) * 2003-10-15 2005-04-28 University Of Tennessee Research Foundation Composes substitues par haloacetamide et azide, et methodes d'utilisation des composes
US20050137172A1 (en) * 2003-10-15 2005-06-23 Dalton James T. Haloacetamide and azide substituted compounds and methods of use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037205A2 (fr) * 2003-10-15 2005-04-28 University Of Tennessee Research Foundation Composes substitues par haloacetamide et azide, et methodes d'utilisation des composes
US20050137172A1 (en) * 2003-10-15 2005-06-23 Dalton James T. Haloacetamide and azide substituted compounds and methods of use thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011002184A2 (fr) * 2009-06-30 2011-01-06 Hanmi Pharm. Co., Ltd. Ester d’acide phosphorique de bicalutamide pour traiter le cancer de la prostate
WO2011002184A3 (fr) * 2009-06-30 2011-04-21 Hanmi Pharm. Co., Ltd. Ester d'acide phosphorique de bicalutamide pour traiter le cancer de la prostate

Also Published As

Publication number Publication date
CN101735267A (zh) 2010-06-16

Similar Documents

Publication Publication Date Title
JP2021183628A (ja) カルビドパおよびｌ−ドーパプロドラッグならびにそれらの使用方法
JP2017128605A (ja) 抗ウイルス化合物の固体形態
TWI826446B (zh) Tlr7/tlr8抑制劑之晶型
JP6675310B2 (ja) アラムコール塩
WO2020020267A1 (fr) Composé de pyridone polycyclique substitué et promédicament correspondant
JP2007302658A (ja) イマチニブメシレートの多形フォーム及び新規結晶フォーム及び非晶フォーム並びにフォームαの調製方法
US11420949B2 (en) Cystine diamide analogs for the prevention of cystine stone formation in cystinuria
ES2909390T3 (es) Formas sólidas cristalinas de sales de N-{4-[(6,7-dimetoxiquinolin-4-il)oxi]fenil}-N'-(4-fluorofenil)ciclopropano-1,1-dicarboxamida, procedimientos de fabricación y procedimientos de uso
EP4050008A1 (fr) Composé de pyridazinone ou de pyridazine et dérivé et composition pharmaceutique de celui-ci
WO2016000568A1 (fr) Composé pour le traitement de la goutte
WO2011140816A1 (fr) Dérivé d'ester de thiénopyridine contenant du nitrile, procédé de préparation, utilisation et composition associés
WO2014059702A1 (fr) Polymorphes de la benfotiamine, leur procédé de préparation et leur utilisation
KR20070119037A (ko) 아르모다피닐의 신규한 결정질 형태 및 이것의 제조 방법
KR20200119786A (ko) 간 전달 엔테카비어 프로드러그 뉴클레오티드 시클로 포스페이트 화합물 및 응용
CN111372579A (zh) 取代的苯基磺酰基苯基三唑硫酮和其用途
WO2010054565A1 (fr) Promédicament hydrosoluble du (r)-(-)-bicalutamide, son procédé de préparation et ses utilisations
JP2019509306A (ja) Ｊａｋ関連疾患の治療又は予防に用いる薬物の塩酸塩の結晶形及びその製造方法
JP2022523385A (ja) アクリル含有核輸送モジュレーターおよびその使用
JP2022519081A (ja) ロガラチニブ塩酸塩の一水和物およびその固体状態
JP2017505788A (ja) イオンチャネルモジュレーターの固体形態
JP7241435B2 (ja) 置換ピラゾール系化合物および該当化合物を含む組成物並びにその使用
JP6523782B2 (ja) 新規な結晶性化合物
JP6317358B2 (ja) Ｌ‐リジンを含む（３ｓ，３ｓ’）４，４’‐ジスルファンジイルビス（３‐アミノブタン１‐スルホン酸）の新規結晶相
JP2019089822A (ja) トピロキソスタットの新規結晶形及びその製造方法
CN113840605B (zh) N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(3-异丙基-2-甲基-2h-吲唑-5-基)嘧啶-2-胺盐酸盐的结晶形式及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09825740

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09825740

Country of ref document: EP

Kind code of ref document: A1