WO2008010794A1 - Préparations pharmaceutiques de lazabémide cristallin - Google Patents

Préparations pharmaceutiques de lazabémide cristallin Download PDF

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Publication number
WO2008010794A1
WO2008010794A1 PCT/US2006/027930 US2006027930W WO2008010794A1 WO 2008010794 A1 WO2008010794 A1 WO 2008010794A1 US 2006027930 W US2006027930 W US 2006027930W WO 2008010794 A1 WO2008010794 A1 WO 2008010794A1
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Prior art keywords
lazabemide
composition
hci
crystalline form
formulated
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Ceased
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PCT/US2006/027930
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English (en)
Inventor
Giorgio Soriato
Marco P. Focati
Roberto Brescello
Livius Cotarca
Roberto Giovanetti
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RENAISSANCE MEDICINE LLC
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RENAISSANCE MEDICINE LLC
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Priority to PCT/US2006/027930 priority Critical patent/WO2008010794A1/fr
Publication of WO2008010794A1 publication Critical patent/WO2008010794A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • the present invention relates to crystalline forms of lazabemide HCI and, more particularly, to processes for preparing crystalline forms of lazabemide HCI (N-(2- aminoethyl)-5-chloro-2-pyridinecarboxamide hydrochloride) and to pharmaceutical preparations thereof.
  • Crystalline forms of pharmaceutically active compounds are generally more stable than amorphous forms of the same compounds and as such the crystalline forms as well as the more stable of multiple crystalline forms or polymorphs are generally more suitable as drug candidates (see Gardner et al., Nature Rev. Drug Disc. 3: 926-934, 2004).
  • Lazabemide HCI has been shown to be a monoamine oxidase inhibitor useful in the treatment of diseases such as Alzheimer's disease and Parkinson's disease (U.S. Patents Nos.4,764,522 and 5,534,635; Cesura et al., Adv. Neurol. 80:521-528, 1999; LeWitt, Neurology 63:S23-S31, 2004).
  • the present invention is directed to pharmaceutical preparations of substantially pure crystalline forms of lazabemide HCI and to methods for the production of the pharmaceutical preparations. Further, the present invention provides new methods for the preparation crystalline forms of lazabemide HCl.
  • the present invention includes pharmaceutical compositions of lazabemide HCI.
  • the compositions can comprise lazabemide HCI, substantially all of which is in crystalline Form A; and one or more pharmaceutically acceptable excipients.
  • the lazabemide HCI has been selected as a component of the composition on the basis of substantially all of the lazabemide HCI being in crystalline Form A.
  • the present invention also includes methods of preparing a pharmaceutical composition. The methods can comprise combining lazabemide HCI substantially all of which is in crystalline Form A and one or more pharmaceutically acceptable excipients.
  • the methods can comprise selecting a composition of lazabemide HCI on the basis of the composition being substantially crystalline Form A of lazabemide and combining the composition with one or more pharmaceutically acceptable excipients.
  • the method can comprise (a) providing an amount of lazabemide HCI; (b) determining the crystalline form of the lazabemide HCI; and combining the lazabemide HCI with one or more pharmaceutically acceptable excipients if the crystalline form of the lazabemide HCI is substantially all Form A.
  • the lazabemide HCI can be at least 99% w/w in crystalline form A
  • the composition can be formulated for oral administration such as in the form of a tablet and the one or more pharmaceutically acceptable excipients can be lactose.
  • Figure 1 illustrates the infrared spectrum of polymorphic Form A produced by the process described below in Example 2.
  • Figure 2 illustrates the differential scanning calorimetry of polymorphic Form A produced by the process described below in Example 2.
  • Figure 3 illustrates the X-ray powder diffraction spectrum of polymorphic Form A produced by the process described below in Example 2.
  • the present invention relates to pharmaceutical compositions of lazabemide HCI crystalline Form A and to processes for their preparation in which the lazabemide HCI in the composition is substantially all in the form of crystalline Form A.
  • Reference to "substantially all" of the lazabemide HCI being in crystalline Form A is intended to mean from about 80% to about 100% w/w or any percent therebetween, of the lazabemide HCI is in crystalline Form A, including at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w, at least 99% w/w or at least about 99.5% w/w.
  • Reference to percent "w/w” or “by weight” or “on a weight bases” is intended to represent the percent of a substance in a composition on the basis of the weight of the substance with respect to the total weight of the composition.
  • lazabemide HCI for use in the pharmaceutical compositions of the present invention can be produced by any of a number of processes.
  • lazabemide HCI can be produced by the process disclosed herein which can be generally characterized as involving the reaction of 2-cyano-5-chloropyridine with 1 ,2-diaminoethane to produce a 2-(5-chloropyridine-2-yl)-1H-imidazoline intermediate followed by hydrolyzing the 2-(5-chloropyridine-2-yl)-1H-imidazoline to produce lazabemide free base. Thereafter, lazabemide HCI can be formed by reacting the free base with HCI.
  • Lazabemide HCI can be precipitated from the reaction mixture by adding an antisolvent.
  • the Lazabemide HCI can be precipitated with methyl te/if-butyl ether (MTBE). Recrystallization of the Lazabemide HCI by dissolving in methanol and precipitating the lazabemide HCI with MTBE produces crystalline Form A of lazabemide HCI in substantial polymorphic purity.
  • Lazabemide HCI in crystalline Form A has an inhibitory activity on monoamine oxidase B.
  • lazabemide is suitable for treatment of various neural conditions such as Parkinson's disease and Alzheimer's disease.
  • Crystalline Form A of lazabemide HCI can be used to prepare pharmaceutical compositions or pharmaceutical preparation.
  • the pharmaceutical compositions or pharmaceutical preparations can comprise a therapeutically effective amount of lazabemide crystalline Form A and a pharmaceutically acceptable excipient.
  • excipient refers to a pharmaceutically acceptable, inactive substance used as a vehicle for a medicament or active ingredient in forming a pharmaceutical composition. Excipients can also aid the process by which a pharmaceutical composition is manufactured. Excipients can include vehicles, carriers, diluents, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors or colors and preservatives.
  • compositions of the present invention are in a pharmaceutically acceptable formulation.
  • Such pharmaceutically acceptable formulations can comprise one or more pharmaceutically acceptable excipients and/or other active ingredients.
  • Formulation of the compositions of the present invention can be achieved by various methods known in the art. A general discussion of these methods may be found in, for example, Hoover, John E., Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA: 1975) which is incorporated herein by reference. See also, Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N.Y., 1980) which is incorporated herein by reference.
  • the preferred pharmaceutical preparation depends on the route of administration. Any route of administration may be used as long as the lazabemide is available via that route. Often suitable routes of administration include, for example, oral, parenteral, inhalation, rectal, nasal, topical (e.g., transdermal and intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual, and intestinal administration.
  • routes of administration include, for example, oral, parenteral, inhalation, rectal, nasal, topical (e.g., transdermal and intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratrach
  • compositions that may be used in conjunction with lazabemide HCI are well known to those of ordinary skill in the art. Excipients can be selected based on a number of factors including, for example, the lazabemide HCI crystalline From A itself; the compound's concentration, stability, and intended bioavailability; the condition being treated; the subject's age, size, and general condition; the route of administration; etc.
  • a general discussion related to carriers may be found in, for example, J. G. Nairn, Remington's Pharmaceutical Science, pp. 1492 1517 (A. Gennaro, ed., Mack Publishing Co., Easton, Pa. (1985), which is incorporated herein by reference.
  • Solid dosage forms for oral administration include, for example, capsules, tablets, gelcaps, pills, dragees, troches, powders, granules, and lozenges.
  • the lazabemide HCI can be combined with one or more excipients.
  • the lazabemide HCI can be mixed with excipients such as lactose, sucrose, starch powder, corn starch, potato starch, magnesium carbonate, microcrystalline cellulose, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, sodium carbonate, agar, mannitol, sorbitol, sodium saccharin, gelatin, acacia gum, alginic acid, sodium alginate, tragacanth, colloidal silicon dioxide, croscarmellose sodium, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • excipients such as lactose, sucrose, starch powder, corn starch, potato starch, magnesium carbonate, microcrystalline cellulose, cellulose esters of alkanoic acids, cellulose alkyl esters, talc
  • Such capsules or tablets can contain a controlled release formulation, as can be provided in a dispersion of the compound or salt in hydroxypropylmethyl cellulose.
  • the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can, for example, include a coating (e.g., an enteric coating) to delay disintegration and absorption.
  • the concentration of lazabemide HCI Form A in a solid oral dosage form can be from about 5 and about 50%, from about 8 to about 40 % or from about 10 to about 30% by weight based on the total weight of the composition.
  • the dosage form is prepared in unit doses of from about 10 mg to about 400 mg, from about 20 mg to about 200 mg and from about 50 mg to about 100 mg of lazabemide HCI Form A.
  • tablets or capsules can be prepared to contain about 50 mg, about 100 mg, about 200 mg or about 400 mg of lazabemide HCl Form A.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents. The concentration of the compound preferably can be from about 0.01 to about 10 mg per ml of the composition. In certain embodiments, the oral compositions can be formulated in solid form for addition of water or other aqueous or nonaqueous liquid prior to use.
  • compositions of this invention for various purposes generally known in the pharmaceutical industry. These components tend to impart properties that, for example, enhance retention of lazabemide HCI at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the lazabemide HCI into pharmaceutical formulations, and the like.
  • cryoprotective agents include cryoprotective agents; agents for preventing reprecipitation of the compound or salt surface; active, wetting, or emulsifying agents (e.g., lecithin, polysorbate 80, TWEEN 80, pluronic 60, and polyoxyethylene stearate); preservatives (e.g., ethyl p-hydroxybenzoate); microbial preservatives (e.g., benzyl alcohol, phenol, m cresol, chlorobutanol, sorbic acid, thimerosal, and paraben); agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate, etc.); agents for adjusting osmolarity (e.g., glycerin); thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose,
  • Suppositories for rectal administration can be prepared by, for example, mixing the drug with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, such as cocoa butter; synthetic mono , di , or triglycerides; fatty acids; and/or polyethylene glycols.
  • compositions for transdermal administration are also contemplated.
  • the compositions can comprise a semi-solid formulation base containing solid micronized drug.
  • parenteral compositions such as, for example, compositions for intravenous or subcutaneous administration, can be formulated in a solid form.
  • Such solid dosage forms can be prepared in a container such as a sealed ampoule for addition of a liquid vehicle prior to use.
  • the liquid vehicle can, in certain embodiments, accompany the solid dosage form in a separate container from that of the solid dosage form and together the solid dosage form and the vehicle can comprise a kit for preparation of the final formulation for parenteral administration.
  • Injectable parenteral preparations can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • Acceptable vehicles for parenteral use include both aqueous and nonaqueous pharmaceutically acceptable solvents
  • Suitable pharmaceutically acceptable aqueous solvents include, for example, water, saline solutions, dextrose solutions (e.g., such as DW5), electrolyte solutions, etc.
  • Suitable pharmaceutically-acceptable nonaqueous solvents include, for example, the following (as well as mixtures thereof): alcohols (these include, for example, ⁇ -glycerol formal, ⁇ -glycerol formal, 1 , 3-butyleneglycol, aliphatic or aromatic alcohols having from 2 to about 30 carbons (e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuranyl alcohol, lauryl alcohol, cetyl alcohol, and stearyl alcohol), fatty acid esters of fatty alcohols (e.g., polyalkylene glycols, such as polypropylene glycol and polyethylene glycol), sorbitan, sucrose, and cholesterol); amide
  • Examples include diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether), and glycofurol (tetrahydrofurfuranyl alcohol polyethylene glycol ether); ketones (these typically have from about 3 to about 30 carbons. Examples include acetone, methyl ethyl ketone, methyl isobutyl ketone); hydrocarbons (these are typically aliphatic, cycloaliphatic, and aromatic hydrocarbons having from about 4 to about 30 carbons.
  • oils examples include benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), and tetramethylenesulfoxide); oils (these include oils of mineral, vegetable, animal, essential, or synthetic origin.
  • mineral oils such as aliphatic and wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil
  • vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, com germ, sesame, persic, and peanut oil
  • glycerides such as mono-, di-, and triglycerides
  • animal oils such as fish, marine, sperm, cod-liver, haliver, squalene, squalane, and shark liver oil
  • oleic oils and polyoxyethylated castor oil
  • alkyl, alkenyl, or aryl halides these include alkyl or aryl halides having from 1 to about 30 carbons and one or more halogen substituent.
  • Examples include methylene chloride); monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (SOLUTOL HS-15, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; and sorbitan monooleate.
  • Other pharmaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art.
  • Preferred solvents include those known to stabilize the compound(s) or salt(s) of interest.
  • oils rich in triglycerides such as safflower oil, soybean oil, and mixtures thereof
  • alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., CREMOPHOR EL solution or CREMOPHOR RH 40 solution).
  • triglycerides include INTRALIPID emulsified soybean oil (Kabi Pharmacia Inc., Sweden), NUTRALIPID emulsion (McGaw, Irvine, California), LIPOSYN Il 20% emulsion (a 20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, IL), LIPOSYN III 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, IL), natural or synthetic glycerol derivatives containing the docosahexaenoyl group at levels of from about 25 to about 100% (by weight based on the total fatty acid content) (DHASCO from Martek Biosciences Corp., Columbia, MD; DHASCO from Mar
  • compositions of the present invention can be used to treat various diseases and conditions including Alzheimer's disease, Parkinson's disease and smoking cessation.
  • the pharmaceutical formulations of the present invention can contain at least one additional active pharmaceutical agent.
  • additional active agents can be selected based upon combined actions of the lazabemide HCI and the additional agents and/or based upon the disease intended for treatment.
  • the pharmaceutical composition of the present invention can comprise (a) lazabemide HCI, substantially all of which is in crystalline Form A; (b) one or more pharmaceutically acceptable excipients and (c) at least one additional active pharmaceutical agent.
  • the additional agent can be a cholinesterase inhibitor such as donepezil hydrochloride (ARICEPT®), rivastigmine (EXELON®) or galantamine (RAZADYNE®), an N-methyl-D-aspartate (NMDA) receptor antagonist such as, for example, memantine (NAMENDA®) or remacemide hydrochloride a dopamine receptor agonist such as, for example ropinirole hydrochloride or levadopa or another active pharmaceutical agent.
  • a cholinesterase inhibitor such as donepezil hydrochloride (ARICEPT®), rivastigmine (EXELON®) or galantamine (RAZADYNE®
  • NMDA N-methyl-D-aspartate
  • NAMENDA® memantine
  • remacemide hydrochloride a dopamine receptor agonist
  • ropinirole hydrochloride or levadopa or another active pharmaceutical agent eXAMPLES
  • a reactor equipped with external cooler was charged under nitrogen flow with 1800 grams (12.99 moles) of ⁇ -chloro ⁇ -cyanopyridine, 46.8 grams (0.2 moles) of p- toluenesulfonic acid monohydrate and 6600 grams of toluene.
  • the mixture was heated to 95°-100°C. Over a period of 2-3 hours, 858.2 grams (14.28 moles) of ethylenediamine were added. Formation and evolution of ammonia occurred during the addition which was controlled by the addition rate.
  • the mixture was maintained at 95-100 0 C for 2 hours and then heated to reflux at 110-114 0 C for 4 hours.
  • the mixture was cooled to about 70 0 C and thereafter maintained at a temperature greater than 55°C. 3600 grams of diethyl acetate and subsequently, 350 grams of demineralized water were added. The mixture was heated to 65 ⁇ 2°C and vigorously stirred for 15-30 minutes. Stirring was stopped and after 15-30 minutes, the lower aqueous layer was discarded. 350 grams of demineralized water was then added and the mixture was heated again to 65 ⁇ 2°C with vigorous stirring for 15-30 minutes. Stirring was stopped and after 15-30 minutes, the lower aqueous layer was again discarded. The mixture was then cooled to 53-55 0 C and the temperature maintained until a precipitate was formed.
  • the material was then cooled to 0 ⁇ 2°C in about 2 hours. Thereafter, a temperature of 0 ⁇ 2°C was maintained for about 30 minutes and the solids were filtered and washed twice with a mixture of 1440 grams of toluene and 720 grams of ethyl acetate cooled to 0 ⁇ 2°C. About 2400 grams of wet solid were obtained. The product was then vacuum dried at 45°C to constant weight and 2075 grams of 2-(5-chloropyridine-2-yl) ⁇ 1-H-imidazoline were obtained (88% yield).
  • a reactor was charged with 6225 grams of demineralized water and 33.2 grams (0.25 moles) of sodium hydroxide. After a few minutes under stirring, 2075 grams (11.43 moles) of 2-(5-chloropyridine-2-yl)-1 H-imidazoline were added and the mixture was heated to reflux under vigorous stirring for 4 hours. Upon completion of the reaction, the mixture was cooled to 65 - 70 0 C and 17.5 grams (0.29 moles) of acetic acid were added. Water was vacuum distilled until internal temperature reached 70 - 80 0 C. The reactor was then vented with nitrogen and 3458 grams of ethanol denatured with cyclohexane/methanol (hereinafter referenced as denatured ethanol) were added.
  • denatured ethanol ethanol denatured with cyclohexane/methanol
  • the reactor was then charged with 6225 grams of denatured ethanol and the mixture was heated and refluxed for 30 minutes. The mixture was then cooled to 20 - 25 0 C and 20.7 grams of charcoal were added. The mixture was stirred and maintained at 20 - 25°C for 30 minutes. The solution containing the lazabemide free base was then filtered through a cake formed by 48.5 grams of celite. The reactor and cake were washed with 1038 grams of denatured ethanol and the filtered solutions combined.
  • the combined filtered solutions were assayed using HPLC/MS (Agilent Technologies, Palo Alto CA) with ESI source (positive mode) ion trap analyzer (ID R-HMS- 01); column: polarity dC18, 5 ⁇ m, 4.6 x 150 mm; mobile phase A: water + 0.05% trifluoroacetic acid; and mobile phase B: acetonitrile + 0.05% trifluoroacetic acid.
  • the combined solutions were determined to contain 2167 grams (10.86 moles) of lazabemide free base and this was added to a reactor. 6225 grams of denatured ethanol were added and the mixture was heated to about 40 ⁇ 2 0 C.
  • This example illustrates an alternative method for the production of crystalline Form A of lazabemide HCI.
  • Lazabemide free base can be produced by processes performed as described below. Hydrolysis of 2-(5-chloropyridine-2-yl)-1 H-imidazoline was carried in water (7.5g per g of substrate) with a catalytic amount of sodium hydroxide (0.04 moles per mole of substrate). The reaction mixture was heated to reflux for two hours, cooled to room temperature and, after addition of sodium chloride aqueous saturated solution, the product was extracted with dichloromethane. The organic phase was dehydrated with sodium sulphate and then vacuum distilled. A waxy solid was obtained, having 99% assay with a yield of about 96%.
  • the reaction can be performed as follows using 3 g of water per g substrate and 0.02 moles sodium hydroxide per g substrate and vacuum distillation which is possible because lazabemide free base is liquid at temperatures higher than 35°C.
  • sodium hydroxide was neutralized with an equimolar quantity of hydrochloric acid or acetic acid. Thereafter, the aqueous phase was distilled under reduced pressure. An azeotrope-forming solvent was added and the mixture was vacuum distilled again. Ethanol solvent was added to the crude solid, inorganic salts were filtered off and crude lazabemide HCI free base was recovered. Yield was 89% based upon lazabemide free base.
  • This material was then characterized by IR powder spectrum, differential scanning calorimetry, and X-ray powder diffraction as described below.
  • This example illustrates the characterization of lazabemide HCI crystalline Form A using infrared spectroscopy, differential scanning calorimetry and X-ray powder diffractometry.
  • One thousand gelatin capsules containing 100 mg of lazabemide HCI crystalline Form A could be manufactured, for example, as follows:
  • polyethylene glycol 6000 10 g
  • demineralized water q.s.

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

Abstract

La présente invention concerne des compositions pharmaceutiques de la Forme cristalline A du lazabémide HCl, ainsi que leurs méthodes de production.
PCT/US2006/027930 2006-07-18 2006-07-18 Préparations pharmaceutiques de lazabémide cristallin Ceased WO2008010794A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501816B2 (en) 2010-10-12 2013-08-06 Cerecor, Inc. Antitussive compositions comprising memantine

Citations (2)

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Publication number Priority date Publication date Assignee Title
US4764522A (en) * 1984-08-29 1988-08-16 Hoffmann-La Roche Inc. Ethylenediamine monoamides
US5534635A (en) * 1989-02-28 1996-07-09 Hoffmann-La Roche Inc. Process for preparing pyridine-2-carboxamides

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US4764522A (en) * 1984-08-29 1988-08-16 Hoffmann-La Roche Inc. Ethylenediamine monoamides
US5534635A (en) * 1989-02-28 1996-07-09 Hoffmann-La Roche Inc. Process for preparing pyridine-2-carboxamides

Non-Patent Citations (5)

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Title
DATABASE CA [online] SUZUKI ET AL.: "Physicochemical Properties and Stability of Lazabemide Hydrochloride", accession no. STN Database accession no. (1994:708127) *
DAVIS P.P. ET AL.: "Determination of Ro 19-6327 (Lazabemide) in Human Plasma and Urine by Gas Chromatography-Negative Chemical Ionization Mass Spectrometry", JOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL APPLICATIONS, vol. 665, 1995, pages 327 - 335 *
LEWITT P. ET AL.: "Clinical Trials of Neuroprotection for Parkinson's Disease", NEUROLOGY, vol. 63, no. 2, SUPPL., October 2004 (2004-10-01), pages S23 - S31 *
MASON R.P. ET AL.: "Antioxidant Activity of the Monoamine Oxidase B Inhibitor Lazabemide", BIOCHEMICAL PHARMACOLOGY, vol. 60, no. 5, 2000, pages 709 - 716 *
vol. 25, no. 8, 1994, pages 690 - 703 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501816B2 (en) 2010-10-12 2013-08-06 Cerecor, Inc. Antitussive compositions comprising memantine

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