WO2013013060A1 - Dérivés d'agomélatine - Google Patents

Dérivés d'agomélatine Download PDF

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Publication number
WO2013013060A1
WO2013013060A1 PCT/US2012/047432 US2012047432W WO2013013060A1 WO 2013013060 A1 WO2013013060 A1 WO 2013013060A1 US 2012047432 W US2012047432 W US 2012047432W WO 2013013060 A1 WO2013013060 A1 WO 2013013060A1
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WIPO (PCT)
Prior art keywords
ethyl
methoxynaphthalen
acetyl
acetamide
butyl
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PCT/US2012/047432
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English (en)
Inventor
Ramesh Sesha
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Lycus, Llc
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Publication of WO2013013060A1 publication Critical patent/WO2013013060A1/fr

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids

Definitions

  • Agomelatine, compound (A) is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist.
  • Agomelatine has been marketed for the treatment of major depressive disorders and reported to have a reduced level of sexual side effects, as well as discontinuation effects, compared to other antidepressants. Agomelatine can also have positive effects on sleep associated with a number of disorders. Agomelatine is indicated for the treatment of major depressive episodes in adults.
  • the patents disclose several compounds of naphthalene structure including agomelatine, their pharmaceutical composition and a method for treating a living animal afflicted with treatable disorder of the melatonergic system.
  • Agomelatine is been reported to re- synchronize circadian rhythms, based on animal models of delayed sleep phase syndrome and other circadian rhythm disruptions. It has been reported to increase noradrenaline and dopamine release specifically in the frontal cortex and has no known influence on the extracellular levels of serotonin. Agomelatine has also been reported to provide an antidepressant-like effect in animal depression models (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm de-synchronization and in models related to stress and anxiety.
  • agomelatine has been reported to provide positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.
  • Agomelatine is also reported to cause fewer sexual side effects and discontinuation effects than sertraline and paroxetine. Additionally, possibly because of its action on melatonin receptors, agomelatine is reported to improve sleep quality, with no reported daytime
  • Agomelatine is poorly soluble in water and has very poor bioavailability (less than 20%) when formulated as orally dispersible tablets.
  • This invention provides novel melatonergic modulating compounds that meet these needs.
  • the present invention provides, in one aspect, compounds which are melatonergic agonists (MT1 and MT2 receptors) and 5-HT2C antagonists. Accordingly, there is provided compounds of Formula (I):
  • R is -COR 1 ; -CO(CHR 2 )NH 2 ; -COO(CHR 3 )OCOR 4 ; -S0 2 R 5 ; -S0 2 NR 6 R 7 , or -CH 2 NHCOPh;
  • R 1 is methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-nitrophenyl or 4-methylphenyl;
  • R 2 is hydrogen, methyl, z ' so-propyl, z ' so-butyl, benzyl, imidazole-4-methyl or
  • R 3 and R 4 are independently methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, tert-butyl, cyclohexyl, cyclopentyl, cyclobutyl, or cyclopropyl;
  • R 5 is methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, tert-butyl, trifluoromethyl, benzyl; phenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 4-fluoro- phenyl, 4-methylphenyl or 4-methoxyphenyl;
  • R 6 and R 7 which may be same or different, and are independently hydrogen, ethyl, tert-butyl, z ' so-butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, benzyl or - CH(CH 3 )Ph;
  • R 8 is methyl, ethyl, n-propyl, or 1-methylethyl (isopropyl), and
  • R 9 is methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, n-pentyl, t- butyl (1,1-dimethylethyl), or phenyl;
  • R 1 is methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-bromophenyl, 4- cyanophenyl, 4-nitrophenyl or 4-methylphenyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides compounds of formula (III):
  • R is hydrogen, methyl, z ' so-propyl, z ' so-butyl, benzyl, imidazole-4-methyl or indole-3 -methyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides compounds of formula (IV):
  • R 3 and R 4 are independently methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, iso- butyl, tert-butyl, cyclohexyl, cyclopentyl, cyclobutyl, or cyclopropyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides compounds of the formula (V):
  • R 5 is from methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, tert-butyl, trifluoromethyl, benzyl, phenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-amino- phenyl, 4-fluorophenyl, 4-methylphenyl or 4-methoxyphenyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides compounds of the formula (VI):
  • R 6 and R 7 which may be same or different, and are independently hydrogen, ethyl, tert-butyl, z ' so-butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl, benzyl or -CH(CH 3 )Ph;
  • the present invention provides compounds having formula (VII)
  • the disclosed compounds and methods are directed to melatonergic agonists (MT1 and MT2 receptors) and 5-HT 2 c antagonists that have activity as selective inhibitors of the MT1 and MT2 receptors or have activity as 5-HT 2 c antagonists.
  • the invention provides a compound of any of the Formulae, I, II, III, IV, V, VI, VII, or a pharmaceutically acceptable salt thereof, for use in medical treatment for example treatment of disorders such as, major depressive disorders, or re-synchronization of circadian rhythms in a mammalian species (for example, a human).
  • the invention provides pharmaceutical compositions including the disclosed compounds of Formulae, I, II, III, IV, V, VI, VII, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. More particularly, the disclosed compounds can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents and stabilizers known to those skilled in the art.
  • compositions comprising a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII, or a pharmaceutically equivalent salt thereof, for treating pain and pain related sleep disorders.
  • the disclosed compositions can be formulated for any route of administration (e.g., the formulations described herein) and can be administered in a single dose or multiple doses to a subject in need thereof.
  • the present invention provides Methods for treating pain and pain related sleep disorders comprising a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII, or a pharmaceutically equivalent salt thereof, to a patient in need thereof.
  • the disclosed method includes administration of compositions formulated for any route of administration (e.g., the formulations described herein) and can be administered in a single dose or multiple doses to a subject in need thereof.
  • composition that comprises "an” element means one element or more than one element.
  • pharmaceutically-acceptable salt refers to salts which retain the biological effectiveness and properties of the disclosed compounds and which are not biologically or otherwise undesirable.
  • the disclosed compounds are capable of forming acid or base salts by virtue of the presence of amino or carboxyl groups or groups similar thereto.
  • An "effective amount” means an amount sufficient to produce a selected effect.
  • the present invention also provides pharmaceutical compositions including a therapeutically acceptable amount of one of the disclosed compounds. More particularly, such compounds can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents and stabilizers known to those skilled in the art. For example, a pharmaceutical composition including a disclosed compound, analog, derivative, or modification thereof, as disclosed herein, is used to administer the appropriate compound to a subject.
  • the disclosed method includes a kit comprising a compound of Formulae, I, II, III, IV, V, VI, VII, or a pharmaceutically acceptable salt thereof and instructional material that describes administering the inhibitor compound or a composition comprising the inhibitor compound to a cell or a subject.
  • a kit comprising a (preferably sterile) solvent for dissolving or suspending the inhibitor compound or composition prior to administering the compound or composition to a cell or a subject.
  • the subject is a human.
  • the term "instructional material” includes a publication, a recording, a diagram, or any other medium of expression that can be used to communicate the usefulness of the disclosed compounds in the kit for effecting alleviation of the various diseases or disorders recited herein.
  • the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal.
  • the instructional material of the kit may, for example, be affixed to a container which contains a disclosed compound or be shipped together with a container which contains the identified compound. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
  • the disclosed compounds can be in the form of pharmaceutically acceptable salts thereof, such as for example, acid addition salts or base addition salts.
  • pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutylate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate,
  • Acids commonly employed to form acid addition salts are inorganic acids, such as for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • Base addition salts include those derived from inorganic bases, such as for example, ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the starting materials e.g., Agomelatine (CAS number 138112-76-2) are either commercially available or can be prepared by the procedures known in the art. Further, in the schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention.
  • reaction conditions for example, temperature and/or duration of the reaction, which are known in the art, are also within the scope of the present invention. All the isomers of the compounds described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
  • the disclosed compounds having chiral centers may exist in and be isolated in optically active, racemic or enantiomerically enriched forms. It is to be understood that the disclosed compounds encompass any racemic, optically active or stereoisomeric form, or mixtures thereof, of the disclosed compounds, which possess the useful properties disclosed herein, such as the S,R; S,S; R,R; or R,S diastereomers. It is well known in the art how to prepare such optically active forms (for example, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or by chromatographic separation using a chiral stationary phase. In addition, enantiomerically enriched compounds of the invention can also be obtained from enantiomerically enriched precursors. Scheme 1
  • Scheme 1 depicts a general procedure for the preparation of compounds of formula (II).
  • Compounds of formula (II), wherein R 1 is as defined above can be prepared by a process known in the art of organic chemistry. For example, a compound of formula (A) reacts with an appropriate carboxylic acid anhydride or carboxylic acid chloride in the presence of a suitable solvent to afford compound of formula (II).
  • a general procedure for the preparation of compounds of formula (IV), wherein R 3 and R 4 are as defined above, is depicted in Scheme 3.
  • a compound having formula (A) reacts with a 1-chloroalkyl chloro formate (e.g., 1-chloroethyl chloro formate) in the presence of a base and suitable solvent to provide a compound of formula (C).
  • a 1-chloroalkyl chloro formate e.g., 1-chloroethyl chloro formate
  • the coupling of compound (C) with an appropriate carboxylic acid in the presence of a suitable solvent and base afford a compound of formula (IV).
  • a compound of formula (VI), wherein R 6 and R 7 are as defined above can be prepared by reacting compound having formula (A) with thionyl chloride, followed by reaction with an amine of the formula R 6 R 7 NH in a suitable organic solvent.
  • a compound having formula (A) can react, e.g., with dimethylsulfamoyl chloride in the presence of a suitable base and in a suitable solvent to provide a compound of formula (VI) wherein both R 6 and R 7 are methyl.
  • the active ingredient for the disclosed compositions and methods, are compounds of formula I, II, III, IV, V, VI, or VII, and are preferably used in the free amphoteric form.
  • compositions of formula I, II, III, IV, V, VI, or VII that retain the biological effectiveness and properties of the compounds of formula I, II, III, IV, V, VI, or VII, that are not biologically or otherwise undesirable, can also be used and can show superior bioavailability.
  • the term "compound of any of formulae I, II, III, IV, V, VI, or VII" is intended to include the agent, as well as their pharmaceutically acceptable salts.
  • compositions are intended for parenteral, intranasal, topical, oral, buccal, or local administration, such as by a transdermal means, for prophylactic and/or therapeutic treatment.
  • the pharmaceutical compositions are administered parenterally (e.g., by intravenous, intramuscular, or subcutaneous injection), or by oral ingestion, or by topical application at areas affected by pain and pain related sleep disorders.
  • the agent can optionally be mixed with solid, powdered inert ingredients, such as lactose, microcrystalline cellulose, maltodextrin, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • Soft gelatin capsules can be prepared by mixing the active agent with vegetable oil, fat, or other suitable vehicle.
  • Hard gelatin capsules can contain granules of the active agent, alone or in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
  • Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, e.g., solutions or suspensions containing about 0.2-20 wt % of the active agent and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations can optionally contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose or other thickening agents.
  • Liquid preparations for oral administration can also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • the disclosed compounds can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms adapted to the chosen route of administration, e.g. , orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least about 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the precipitated product is filtered, washed with water (2 x 1 mL), and dried by pressing between folds of filter paper. Traces of water are removed in a vacuum desiccator to obtain N-acetyl-N-(2-(7-methoxynaphthalen-l-yl)ethyl)- acetamide, II-A. The yield was 31%.
  • Formula III-C Triethyl amine is added into a solution of N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide in dichloromethane. The mixture is cooled and an activated form of N-Boc-valine (e.g., O-t-butyloxycarbonyl valine) is added. The mixture is stirred for 10-12 hours and quenched the reaction by adding aqueous sodium bicarbonate. The mixture is washed with dilute HC1 (aqueous) and extracted with ethyl acetate. The organic extracts are combined and dried over a desiccant (e.g., magnesium sulfate anhydrous).
  • N-Boc-valine e.g., O-t-butyloxycarbonyl valine
  • the resulting reaction mixture is filtered to remove organic solvent which furnish the tert-butyl (l-(N-(2-(7-methoxy- naphthalen- 1 -yl)ethyl)acetamido)-3 -methyl- 1 -oxobutan-2-yl)carbamate .
  • N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (1 mmol) was mixed with 36 % formaldehyde (2.2 mmol) in a flask equipped with a magnetic stirrer and a condenser. The mixture was heated for 24 hours in a constant temperature bath, at 80°C, for 24 hours. The reaction mixture was decomposed over ice-cooled water and extracted three times with 15 ml of ethyl ether. The combined ether extracts was washed with water and then dry over anhydrous magnesium sulfate.
  • mice were evaluated for their acute toxicity in mice.
  • the animals weighing 16-27 grams were procured from Charles River Laboratories. They were housed in standard cages for six days for acclimatization. The animals were fed at regular intervals all six days and observed by a veterinarian. On day 7, the mice were administered with investigative compound and were observed at regular intervals during the first day and daily during the two weeks following treatment.
  • the LD 50 killing 50% of the animals was evaluated and demonstrated the low toxicity of the compounds of the invention.
  • the disclosed compounds of Formula (I) were evaluated for their receptor binding at MT1 or MT2 receptors by using 2 - [ 125 I]-iodomelatonin as radio ligand reference. A liquid scintillation counter was used to measure the retained radioactivity. The protocol involved performing competitive binding experiments in triplicate, with various test compounds at a range of different concentrations was tested for each compound. The results are used to determine the binding affinities of the compounds tested (Ki).
  • the compound V-L, (N-(2-(7- methoxynaphthalen-l-yl)ethyl)-N-tosylacetamide ) prepared in Example 4 shows a Ki (MT1 ) of 6 nM and a Ki (MT2 ) of 0.5 nM.
  • the Forced swimming Test with mice is a commonly used animal testing model for correlation of the effects of an antidepressant of drug candidates.
  • the compounds of the formula (I) were tested in a Forced swimming Test before and after oral administration of the test compound.
  • the downtime of the animal was recorded in an apparatus consisting of a glass cylinder filled with water. Each animal was tested separately for 5-7 minutes by placing the animal at the center of the apparatus. Again the animal was tested 1 minute after the
  • the compounds of the formula (I) significantly reduce downtime attesting to their antidepressant activity.
  • Circadian rhythms produce daily changes in critical elements of various disorders such as pain, depression and other CNS diseases. Thus, they are a reliable indicator of the activity of the endogenous circadian clock.
  • the pharmacology of melatoninergic compounds are usually evaluated by studying circadian rhythms.
  • the effects of compounds of formula (I) are tested on circadian rhythms of locomotor activity in Rat model.
  • the animals were transferred to experimental cages. Each cage was placed on an Animex (MK-Animex, Muromachi Kikai, Tokyo) to detect locomotor activity. Drinking activity was measured by a drinkometer (O'Hara, Tokyo).
  • the cage and the Animex were placed in a ventilated lightproof cabinet (71 x 46 x 35 cm) illuminated by a krypton bulb (KRlOO/110V40PS35WK, Toshiba Lightech, Tokyo) fixed on the inner wall of the cabinet, which was placed in a temperature-controlled (26 ⁇ 2°C) experimental room.
  • the test compounds of formula (I) were tested in a behavioral model, the test, light / dark cage, allowing the anxiolytic activity of molecules.
  • the light/dark box consisted of a Makrolon type III cage divided into two equally sized compartments: one light compartment painted white on three sides and the fourth side of transparent plastic (to allow video recording), and an open top and one dark compartment painted black on all four sides with a sliding lid on the top to allow for placement of the mouse.
  • a clear Perspex tunnel connected the two compartments.
  • the illumination in the black compartment was 50 lux, in the white area it was increased to 1000 lux, generated by an additional light source. Before each test the box was cleaned with 70% ethanol and wiped with a paper tissue.
  • the mouse was placed in the middle of the dark compartment and was allowed to explore the test apparatus for 5 min. The time spent by mice in the illuminated box and the number of transitions through the tunnel are recorded after the first entry in the dark box. The test compounds were administered 30 minutes before the test. It was shown that the compounds of formula (I) increase of significantly the time spent in the illuminated cage and the number of transitions, which illustrates the anxiolytic activity of the disclosed compounds.
  • a solution of 100 g of a compound of Formula (I) and 5 g of disodium hydrogen phosphate in 3 L of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid.
  • the solution is sterile-filtered, filled into injection vials, lyophilized and sterile-sealed. Each injection vial contains about 5 mg of active ingredient.
  • a mixture of 20 mg of a compound of Formula (I) is melted with 100 g of soya lecithin and 1,400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains about 20 mg of the compound of Formula I.
  • a solution of 1 g of a compound of Formula (I), 9.38 g of NaH 2 P0 4 '2H 2 0, 28.48 g of Na 2 HP0 4 » 2H 2 0 and 0.1 g of benzalkonium chloride is prepared in 940 ml of double-distilled water. The pH is adjusted to 6.8, and the solution is made up with distilled water and sterilized by irradiation. This solution can be used, e.g., as eye drops.
  • a compound of Formula (I), 500 mg, is mixed with 99.5 g of petroleum jelly under aseptic conditions. This provides an ointment with 0.5 % active agent.
  • a mixture of 1 kg of a compound of Formula (I), 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in conventional manner such that each tablet contains about 10 mg of active ingredient.
  • Tablets are prepared and formed by compression as described in Example 17 and covered in conventional manner with a coating prepared, e.g., with sucrose, potato starch, talc, tragacanth and colorant.
  • each capsule contains about 20 mg of the active ingredient.
  • the capsules can also use a composition having optional inactive ingredients, such as those used to from the tablets, etc.
  • a solution of 1 kg of a compound of a Formula (I) in 60 L of double-distilled water is filled into ampoules and lyophilized under aseptic conditions and the ampoules are sealed under sterile conditions. Each ampoule contains about 10 mg of active ingredient.

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Abstract

On décrit des dérivés d'agomélatine présentant des propriétés utiles. Ces dérivés peuvent être utilisés pour la préparation de médicaments.
PCT/US2012/047432 2011-07-19 2012-07-19 Dérivés d'agomélatine WO2013013060A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN104586797A (zh) * 2015-01-05 2015-05-06 万特制药(海南)有限公司 阿戈美拉汀分散片及其制备方法
CN109589313A (zh) * 2017-10-01 2019-04-09 万特制药(海南)有限公司 阿戈美拉汀分散片及其制备方法

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