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WO2006010620A2 - Sels d'olanzapine et leur conversion en bases libres d'olanzapine - Google Patents

Sels d'olanzapine et leur conversion en bases libres d'olanzapine Download PDF

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Publication number
WO2006010620A2
WO2006010620A2 PCT/EP2005/008218 EP2005008218W WO2006010620A2 WO 2006010620 A2 WO2006010620 A2 WO 2006010620A2 EP 2005008218 W EP2005008218 W EP 2005008218W WO 2006010620 A2 WO2006010620 A2 WO 2006010620A2
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WIPO (PCT)
Prior art keywords
olanzapine
solvate
water
process according
mixture
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PCT/EP2005/008218
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English (en)
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WO2006010620A3 (fr
Inventor
Igor Simonic
Roman Lenarsic
Berta Kotar-Jordan
Rok Zupet
Joze Gnidovec
Original Assignee
Krka, Tovarna Zdravil, D.D., Novo Mesto
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.)
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Application filed by Krka, Tovarna Zdravil, D.D., Novo Mesto filed Critical Krka, Tovarna Zdravil, D.D., Novo Mesto
Priority to EP05779020A priority Critical patent/EP1781665A2/fr
Publication of WO2006010620A2 publication Critical patent/WO2006010620A2/fr
Publication of WO2006010620A3 publication Critical patent/WO2006010620A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention belongs to the field of organic chemistry and relates to new salts of 2-methyl-4- (4-methyl-1- piperazinyl) -10H-thieno [2,3-jb] [1,5] benzodiazepine (herein ⁇ after referred to by its generic name "olanzapine”) with acids selected from the group of acetic, benzoic, hydrochloric, ben ⁇ zenesulfonic, and perchloric acid, methods for their produc ⁇ tion, their use for olanzapine purification, and a method for their conversion to polymorphic form I of olanzapine.
  • olanzapine 2-methyl-4- (4-methyl-1- piperazinyl) -10H-thieno [2,3-jb] [1,5] benzodiazepine
  • Olanzapine has shown to have high activity with regard to the central nervous system and is also useful for the treat ⁇ ment of schizophrenia, schizophreniform disorders, acute ma ⁇ nia, mild anxiety states and psychosis.
  • solvents like acetoni- trile are used for the purification of olanzapine free base and for the production of form I.
  • these solvents are not recommended for use in the final steps of preparation of pharmaceuticals since they are harmful. Beside this they often do not lead to satisfactory overall yields of olanzapine form I.
  • these prior art processes often do not lead to olanzapine having a purity which is satisfactory for the preparation of pharmaceutical formulations as impurities are present, which are hard to re ⁇ move according to prior art processes .
  • GB 1 533 235 discloses antipsychotically effective thie- nobenzodiazepines by a generic formula which also covers olan- zapine.
  • EP 0 454 436 describes olanzapine explicitly.
  • the de ⁇ scribed process for its synthesis further involves crystalli- zation from acetonitrile and the melting point of the crystal ⁇ lized compound was determined to be at 195 0 C.
  • EP-B-733 635 claims crystalline form II of olanzapine. This polymorphic form is said to be more stable than the mate- rial obtained according to EP 0 454 436 which is designated "form I olanzapine". Both form I and form II of olanzapine are characterized by e. g. X-ray data.
  • the preparation of the more stable form II of olanzapine is effected by dissolving techni ⁇ cal grade olanzapine in ethyl acetate and crystallization from the resulting solution by any conventional process, such as seeding, cooling, scratching the glass of the reaction vessel or other common techniques.
  • WO 02/18390 discloses the monohydrate form I and the di- hydrate form I of olanzapine, a process for production thereof and a process for production of form I of olanzapine which comprises the steps of stirring olanzapine monohydrate form I or crude olanzapine or form II of olanzapine in methylene chloride at reflux, cooling, filtering and drying. It is also described that a repeating of the process described in EP 0 454 436 Example 1, subexample 4 did not lead to formation of form I of olanzapine.
  • WO 03/101997 relates to processes for the preparation of form I of olanzapine by regulation of the pH-value of the so ⁇ lution.
  • WO 03/055438 discloses crystallization from ethanol and the consequent transformation of the ethanol solvate to poly ⁇ morphic form I of olanzapine.
  • US 5,637,584 discloses the (mono)methylene solvate form ⁇ of olanzapine and a method for its conversion to polymorphic form I of olanzapine.
  • EP-B-733 634 relates to three specific solvates of olan ⁇ zapine namely the methanol, ethanol and 1-propanol solvates and a process for production of form II olanzapine by drying the corresponding solvates.
  • WO 2004/006933 discloses the preparation of form I, some pseudopolymorphic forms, namely isopropanol solvate, acetoni- trile/methylene chloride/water and acetonitrile/water mixed solvates of olanzapine, polymorphic form A, and processes for the preparation thereof.
  • the present invention provides novel salts of 2-methyl-4- (4-methyl-l-piperazinyl) -lOH-thieno [2,3-Jb] [1, 5] benzodiazepine or olanzapine useful as intermediates in the isolation of olanzapine from complex reaction mixtures.
  • These salts can be used for the production of olanzapine base which has suitable purity for pharmaceutical use and can easily be converted to anhydrous olanzapine polymorphic form I, in high yields.
  • olanzapine free base is isolated from reaction mixtures using crystallization from solvents like methylene chloride and ace- tonitrile. These procedures are used for the purification of olanzapine free base and for the production of form I but of- ten they do not lead to satisfactory overall yields of form I of olanzapine. Moreover, these prior art processes often do not lead to olanzapine having a purity which is satisfactory for the preparation of pharmaceutical formulations as impuri- ties are present, which are hard to be removed according to the prior art processes.
  • X represents the acetate, benzoate, chloride, dichlo- ride, benzenesulfonate, or perchlorate anion.
  • the salts of formula II may be prepared with widely used ac- ids, such as acetic, benzoic, hydrochloric, benzenesulfonic and perchloric acid, in a surprisingly simple and efficient way.
  • These salts according to the invention can be isolated with minimal additional steps, after completion of conversion of intermediates to olanzapine, and are well suited for the conversion to olanzapine form I, through olanzapine dichlo- roraethane solvate, of the appropriate purity.
  • the invention provides a process for preparing olanza- pine by using the compound of formula II, i.e. the salts ac ⁇ cording to the invention.
  • the olanzapine prepared can in a first embodiment be a salt of olanzapine which is different from the salts according to the invention.
  • the olanzapine prepared is olanzapine of form I.
  • This is preferably obtained by con ⁇ verting the salts according to the invention to the olanzapine dichloromethane solvate and this solvate is then converted to the desired form I olanzapine. It is also possible to convert the salts first of all to the water isopropanol solvate of olanzapine, then converting this mixed solvate to the olanza ⁇ pine dichloromethane solvate and subsequently converting this solvate to olanzapine of form I.
  • the salts are prepared from a reaction mixture.
  • the particular advantage of the present inven- tion is apparent that, despite the presence of a complex mix ⁇ ture, it is possible to isolate in high purity the salts of the invention which can subsequently be converted to olanza ⁇ pine, preferably form I olanzapine, having also a high purity.
  • the reaction mixture is preferably a mixture which is obtained by the process for preparing olanzapine as disclosed in WO 2004/065390. Explicit reference is made as to the details of this process which therefore become subject matter of the pre ⁇ sent invention.
  • reaction mixture is ob- tained by a reaction which comprises the conversion of the in ⁇ termediate 2,4-bis (4-methyl-1-piperazinyl) -3-propylidene-3H- [1, 5]benzodiazepine or 4-amino-2-methyl-1OH-thieno [2,3- b] [1, 5] benzodiazepine hydrochloride to olanzapine.
  • a reaction which comprises the conversion of the in ⁇ termediate 2,4-bis (4-methyl-1-piperazinyl) -3-propylidene-3H- [1, 5]benzodiazepine or 4-amino-2-methyl-1OH-thieno [2,3- b] [1, 5] benzodiazepine hydrochloride to olanzapine.
  • reaction mixture is treated with an acid selected from acetic, benzoic, hydrochloric, ben- zenesulfonic and perchloric acid. This will lead to formation of the salts according to the invention.
  • the process according to the invention will use the benzoate salt of olanzapine, i.e. X is the benzoate anion in formula II.
  • the invention also provides in a general aspect the use of the salts according to the invention as intermediates for the purification of olanzapine.
  • the invention also provides the use of these salts as interme ⁇ diates for the production of olanzapine isopropanol water sol ⁇ vate, olanzapine dichloromethane solvate, anhydrous olanzapine or olanzapine of form I.
  • the invention also provides a pharmaceutical composition which comprises the salts according to the invention.
  • a pharmaceutical composition which comprises the salts according to the invention.
  • the isolation of the salts can be done by a person skilled in the art exploiting the procedures widely used in the chemical synthesis and in particular in the following ways: After evaporating evaporatable components or solvents from the com- pleted synthetic reaction mixture of olanzapine, extracting of the mixture with an organic solvent and water in order to re ⁇ move water soluble impurities, separating of the water layer from the organic solvent layer, evaporating of the extraction solvent, dissolving the residue in another appropriate solvent or mixture of solvents and adding an acid as such, or a solu ⁇ tion of that acid. After the salt precipitates it is collected by filtration.
  • a solvent or a mixture of sol- vents of low miscibility with water, can preferably be used, e.g. acetates (e.g. methyl, ethyl, n-propyl, i-propyl, or bu ⁇ tyl acetate), chlorinated solvents (e.g. dichloromethane, chloroform or similar solvents), or ethers (e.g. diethyl ether, diisopropyl ether, or t-butyl methyl ether) .
  • chlorinated solvents e.g. dichloromethane, chloroform or similar solvents
  • ethers e.g. diethyl ether, diisopropyl ether, or t-butyl methyl ether
  • a solvent can preferably be selected from the group of lower alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-, i- or t-butanol) , ke- tones (e.g. acetone, methyl ethyl ketone, or diethyl ketone) , nitriles (acetonitrile, or propionitrile) , acetates (e.g. methyl, ethyl, n-propyl, i-propyl, or butyl acetate) or ethers
  • lower alcohols e.g. methanol, ethanol, isopropanol, n-propanol, n-, i- or t-butanol
  • ke- tones e.g. acetone, methyl ethyl ketone, or diethyl ketone
  • nitriles acetonit
  • an organic or inorganic acid can be selected form the group consisting of acetic, benzoic, hydrochloric, benzenesulfonic and perchloric acid.
  • the acid can be in its pure form, or in form of a mixture with a solvent or water.
  • Another procedure of isolation of salts can in particular be effected in the following way: After the evaporation of evaporatable components or solvents from the completed syn- thetic reaction mixture of olanzapine, the extraction of the mixture with an organic solvent and acidified water follows. By this procedure impurities soluble in organic solvent are removed, while olanzapine remains in the water layer. By sepa ⁇ rating the solvent from the water layer, adding a new portion of organic solvent and making the water layer alkaline, olan ⁇ zapine is present in the organic layer.
  • solvents or mixtures of solvents of low miscibility with water can be used, preferably acetates (e.g. methyl, ethyl, n-propyl, i-propyl, butyl ace ⁇ tate) , chlorinated solvents (e.g. dichloromethane, chloroform or similar solvents), or ethers (e.g. diethyl ether, diisopro- pyl ether, t-butyl methyl ether) .
  • acetates e.g. methyl, ethyl, n-propyl, i-propyl, butyl ace ⁇ tate
  • chlorinated solvents e.g. dichloromethane, chloroform or similar solvents
  • ethers e.g. diethyl ether, diisopro- pyl ether, t-butyl methyl ether
  • a solvent can preferably be selected from the group of lower alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-, i- or t-butanol) , ke- tones (e.g. acetone, methyl ethyl ketone, diethyl ketone) , ni- triles (acetonitrile, propionitrile) , acetates (e.g. methyl, ethyl, n-propyl, i-propyl, butyl acetate), or ethers (e.g. di ⁇ ethyl ether, diisopropyl ether, t-butyl methyl ether) , or mix- tures of them, or even their mixtures with water.
  • lower alcohols e.g. methanol, ethanol, isopropanol, n-propanol, n-, i- or t-
  • an organic or inorganic acid can be selected from the group of acetic, benzoic, hydrochloric, benzenesulfonic, and perchloric acid.
  • the acid used can be in pure form, or in form of a mixture with a solvent or water.
  • the water layer can be made alkaline using usual bases employed in organic synthesis, e.g. bases of earth alkaline metals, or organic bases, such as lithium, sodium, potassium, calcium hydroxides, hydrogen carbonates or carbonates, ammo ⁇ nia, trimethyl- or triethylamine.
  • bases of earth alkaline metals e.g. bases of earth alkaline metals, or organic bases, such as lithium, sodium, potassium, calcium hydroxides, hydrogen carbonates or carbonates, ammo ⁇ nia, trimethyl- or triethylamine.
  • the procedure can be simplified in such a way that the extraction solvent is not evaporated, but that the above men- tioned acid or solution of acid is added, after the separation of the water layer, directly into the extraction solution.
  • the procedure can also be simplified further in a way that extraction is omitted, and the above mentioned acid or the solution of the acid is added into the solution of the re ⁇ action mixture, after the evaporation of evaporatable compo ⁇ nents.
  • the solvent can preferably be selected from the group of lower alcohols (e.g. methanol, ethanol, iso- propanol, n-propanol, n-, i- or t-butanol) , ketones (e.g. ace- tone, methyl ethyl ketone, diethyl ketone) , nitriles (acetoni ⁇ trile, propionitrile), or acetates (e.g.
  • a solvent can preferably be selected from the group of lower alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-, i- or t-butanol) , ke ⁇ tones (e.g.
  • acetone methyl ethyl ketone, diethyl ketone
  • ni- triles acetonitrile, propionitrile
  • acetates e.g. methyl, ethyl, n-propyl, i-propyl, butyl acetate
  • mix ⁇ ture of them or even their mixtures with water.
  • the isolation of olanzapine salt can be simplified further such that extraction is omitted.
  • This embodiment is particularly useful for reaction mixtures ob ⁇ tained according to the processes described in WO 2004/065390.
  • the residue is diluted with a high boiling point solvent, mis- proficient with water, e.g. alkylated or partly alkylated glycols, polyglycols or glycerol (e.g.
  • diethylene glycol dimethyl ether triethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol monoethyl ether, glycerol, 1,2-isopropylidene glycerol), dimethyl sulfoxyde, tetrahydro- thiophene-1, 1-dioxyd or mixtures thereof and a low boiling point solvent immiscible with water e.g. dichloromethane, chloroform, isopropyl acetate, diethyl ether, diisopropyl ether, methyl-t-butyl ether, preferably dichloromethane.
  • the filtrate is treated with base, preferably with a hydroxide of a group I and II metal (e.g. sodium hydroxide, lithium hydroxide, potassium hydroxide, mag ⁇ nesium hydroxide, calcium hydroxide, barium hydroxide) .
  • a hydroxide of a group I and II metal e.g. sodium hydroxide, lithium hydroxide, potassium hydroxide, mag ⁇ nesium hydroxide, calcium hydroxide, barium hydroxide
  • the salt of organic acid is filtrated off and the low boiling point solvent of the filtrate is distilled off.
  • organic solvent selected from the group of lower alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-, i-, or t-butanol) , ketones (e.g.
  • acetone methyl ethyl ketone, diethyl ketone
  • nitriles acetonitrile, propionitrile
  • organic or inorganic acid selected from the group of ace ⁇ tic, benzoic, hydrochloric, benzenesulfonic and perchloric acid.
  • the salts prepared in this way can be further purified by recrystallization from appropriate solvents, if necessary.
  • olanzapine salts of the invention which are prepared by the procedures above, can be converted to the olanzapine free base by extraction or crystallization.
  • Extraction can be done using organic solvents and alka ⁇ line water media.
  • alkaline media water solutions of sodium carbonate, sodium hydrogen carbonate, or hydroxide, or potas ⁇ sium equivalents of them can be used.
  • solu ⁇ tions of ammonia or other organic amines can be used as well.
  • extraction solvent a usual extraction solvent as de ⁇ fined above can be used. After the separation of layers, the organic layer is evaporated to the oily residue, which is dis ⁇ solved in an appropriate solvent and crystallized.
  • Crystallization can be done by suspending the olanzapine salt in an appropriate solvent and converting it by adding a base.
  • the form of mixed water isopro- panol solvate is prepared by usual extraction in organic sol ⁇ vents and alkaline water media.
  • alkaline media water solu ⁇ tions of sodium carbonate, sodium hydrogen carbonate, or hy ⁇ droxide, or potassium equivalents of them are used.
  • solutions of ammonia or other organic amines could be used as well.
  • extraction solvent a usual extraction solvent as de ⁇ fined above can be used. After the separation of layers, the organic layer is evaporated to the oily residue, which is dis- solved in isopropanol. The mixed solvate precipitates after the addition of the appropriate amount of water. The procedure can be simplified in the way that the extraction is omitted. In this case the olanzapine salt is suspended in isopropanol. After addition of the appropriate amount of water solution of base, the solid transforms to olanzapine water isopropanol solvate. The product is collected with suction, again. As base again water solutions of sodium carbonate, sodium hydrogen carbonate or hydroxide or potassium equivalents of them can be used.
  • Transformation of olanzapine water isopropanol solvate to dichloromethane solvate is preferably achieved by dissolving olanzapine water isopropanol solvate in dichloromethane, con ⁇ centrating the solution by evaporation and collecting solid olanzapine dichloromethane solvate.
  • the yield of the solvate depends on the proportion between olanzapine and dichlo- romethane.
  • the transformation of olanzapine dichloromethane solvate to olanzapine form I can preferably be effected by slurring solid olanzapine dichloromethane solvate in isopropanol and collecting the solid olanzapine form I by suction.
  • olanzapine form I can be simplified such that the isolation of olanzapine water isopropanol solvate is omitted.
  • the olanzapine salts prepared by the procedures above, can be converted to the olanzapine free base in the form of dichloromethane sol ⁇ vates, such as disclosed in US 5,637,584, WO 2004/006933, and SI P-200400073, by usual extraction using dichloromethane and alkaline water media.
  • alkaline media water solutions of so- dium carbonate, sodium hydrogen carbonate, or hydroxide, or potassium equivalents of them can be used. In place of them solutions of ammonia or other organic amines could be used as well.
  • the organic layer is partially concentrated and the solid olanzapine dichlo- romethane solvate is collected by suction.
  • Dichloromethane as extraction solvent can be replaced by any other usual extrac ⁇ tion solvent as defined above. If the solvent is different from -dichloromethane, then the organic layer must be evapo ⁇ rated first and the residue is dissolved in dichloromethane.
  • Olanzapine dichloromethane formed in this way can pref- erably be converted to olanzapine form I by the method defined above.
  • the present invention is further illustrated by the following Examples.
  • the substance was prepared from 4-amino-2-methyl-10H- thieno [2,3-b] [1, 5] benzodiazepine hydrochloride as above. After extraction, drying and evaporation of the solvent, the residue was dissolved in isopropanol and 0.318 g of benzoic acid was added. The mixture was agitated overnight and the product was collected by suction. After drying, the yield was 0.64 g.
  • the IR spectrum was identical to the spectrum of the substance prepared by the Example 3.
  • the precipitate was filtered off and washed with dichloromethane and 2- propanol (15 ml, 1 : 1) .
  • the filtrate was extracted with HCl (50 ml, 0.5 M) .
  • the organic phase was diluted with dichlo ⁇ romethane and 2-propanol (100 ml, 1 : 1) and extracted with HCl (50 ml, 1 M) .
  • the organic phase was again extracted with HCl (50 ml, 2M) .
  • the combined aqueous phases were made alka ⁇ line with 5 M NaOH at a pH of 10, and extracted with dichlo- romethane (150 ml) .
  • Benzoic acid (1.832 g, 15 mmol) was added to the organic phase.
  • the solution was concentrated to form an oily residue and suspended in isopropyl acetate.
  • the solid was collected by suction and dried.
  • the IR spectrum was identical to the spectrum of the substance prepared in Example 3.
  • Example 10 The mixture of 3 g of 4-amino-2-methyl-1OH-thieno [2, 3- b] [1, 5]benzodiazepine hydrochloride (about 92% purity) , 4 ml of dimethyl sulfoxide, 13.5 ml of toluene, and 10.5 ml of N- methylpiperazine was refluxed for 4 hours, cooled and water was added. The mixture was extracted with 30 ml of isopropyl acetate. The organic layer was washed with brine and 1 ml of concentrated hydrochloric acid was added. After the separation of the oily product, 10 ml of isopropanol was added, and the mixture was agitated overnight.
  • Example 20 2.0 g of olanzapine water isopropanol mixed solvate, prepared by the procedure as described in Example 17, were dissolved in 24 ml of dichloromethane. The solution was concentrated to about 1/5 of the starting volume by distillation. After col- lecting the product by filtration and drying in vacuum at room temperature to a constant weight, the yield was 1.6 g. The IR spectrum corresponds to the spectrum of the previous Example.

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Abstract

L'invention porte sur des sels d'olanzapine intermédiaires utiles de conversion pour isoler l'olanzapine de mélanges réactifs complexes. Lesdits sels peuvent servir à la production de bases d'olanzapine d'une pureté suffisante pour être employées en pharmacie et pouvant facilement être converties avec de forts rendements en la forme 1 polymorphe de l'olanzapine anhydre.
PCT/EP2005/008218 2004-07-28 2005-07-28 Sels d'olanzapine et leur conversion en bases libres d'olanzapine WO2006010620A2 (fr)

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SIP-200400219 2004-07-28
SI200400219A SI21850A (sl) 2004-07-28 2004-07-28 Soli olanzapina in njihova pretvorba v prosto bazo olanzapina

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WO2006010620A3 WO2006010620A3 (fr) 2006-06-08

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007032695A1 (fr) * 2005-09-15 2007-03-22 Thomasz Kozluk Sels nouveaux d'olanzapine et leur procédé de préparation
WO2008007081A1 (fr) * 2006-07-10 2008-01-17 Cenes Limited Sels de benzodiazépine et leurs formes polymorphes à action brève
WO2008007071A1 (fr) * 2006-07-10 2008-01-17 Cenes Limited Sels de benzodiazépine et leurs formes polymorphes à action brève
US7323459B2 (en) 2002-12-24 2008-01-29 Teva Pharmaceutical Industries Ltd. Crystal forms, methods for their preparation and method for preparation of olanzapine
WO2008091169A2 (fr) 2007-01-22 2008-07-31 Tomasz Kozluk Nobilus Ent Procédé de préparation de la forme polymorphe i d'olanzapine sensiblement pure
US8106188B2 (en) 2006-06-01 2012-01-31 Aurobindo Pharma Ltd Process for preparing olanzapine form I
US10195210B2 (en) 2010-11-08 2019-02-05 Paion Uk Ltd. Dosing regimen for sedation with CNS 7056 (Remimazolam)
US10414749B2 (en) 2013-03-04 2019-09-17 Paion Uk Limited Process for preparing 3-[(S)-7-bromo-2-((2-oxopropyl)amino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionic acid methyl ester
EP4146656A4 (fr) * 2020-05-05 2024-06-26 Syneurx International (Taiwan) Corp. Sels de neuroceutiques et leurs utilisations

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EP0454436A1 (fr) * 1990-04-25 1991-10-30 Lilly Industries Limited Composés pharmaceutiques
US5637584A (en) * 1995-03-24 1997-06-10 Eli Lilly And Company Solvate of olanzapine
WO2003055438A2 (fr) * 2001-12-24 2003-07-10 Sun Pharmaceutical Industries Limited Forme cristalline de 2-methyl-4-(4-methyl-1-piperazinyl) 10h thieno [2,3-b][1,5]benzodiazepine
WO2003101997A1 (fr) * 2002-05-31 2003-12-11 Geneva Pharmaceuticals, Inc. Procédé de préparation d'une forme cristalline i d'olanzapine
WO2004094433A1 (fr) * 2003-04-22 2004-11-04 EGIS Gyógyszergyár Rt. Nouveaux polymorphismes du chlorhydrate d'olanzapine
WO2005070937A1 (fr) * 2004-01-27 2005-08-04 Synthon B.V. Procede de fabrication d'olanzapine sous forme polymorphe i

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Publication number Priority date Publication date Assignee Title
EP0454436A1 (fr) * 1990-04-25 1991-10-30 Lilly Industries Limited Composés pharmaceutiques
US5637584A (en) * 1995-03-24 1997-06-10 Eli Lilly And Company Solvate of olanzapine
WO2003055438A2 (fr) * 2001-12-24 2003-07-10 Sun Pharmaceutical Industries Limited Forme cristalline de 2-methyl-4-(4-methyl-1-piperazinyl) 10h thieno [2,3-b][1,5]benzodiazepine
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US7323459B2 (en) 2002-12-24 2008-01-29 Teva Pharmaceutical Industries Ltd. Crystal forms, methods for their preparation and method for preparation of olanzapine
WO2007032695A1 (fr) * 2005-09-15 2007-03-22 Thomasz Kozluk Sels nouveaux d'olanzapine et leur procédé de préparation
US8106188B2 (en) 2006-06-01 2012-01-31 Aurobindo Pharma Ltd Process for preparing olanzapine form I
CN103288834B (zh) * 2006-07-10 2015-07-15 Paion英国有限公司 短效苯并二氮杂*盐及其多晶型
CN104059071B (zh) * 2006-07-10 2016-06-22 Paion英国有限公司 短效苯并二氮杂*盐及其多晶型
US10961250B2 (en) 2006-07-10 2021-03-30 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
WO2008007071A1 (fr) * 2006-07-10 2008-01-17 Cenes Limited Sels de benzodiazépine et leurs formes polymorphes à action brève
AU2007274054B2 (en) * 2006-07-10 2012-05-24 Paion Uk Limited Benzodiazepine salts
RU2470935C2 (ru) * 2006-07-10 2012-12-27 ПАЙОН ЮКей ЛИМИТЕД Бензодиазепиновые соли кратковременного действия и их полиморфные формы
US8642588B2 (en) 2006-07-10 2014-02-04 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
CN104059072A (zh) * 2006-07-10 2014-09-24 Paion英国有限公司 短效苯并二氮杂*盐及其多晶型
CN104059071A (zh) * 2006-07-10 2014-09-24 Paion英国有限公司 短效苯并二氮杂*盐及其多晶型
WO2008007081A1 (fr) * 2006-07-10 2008-01-17 Cenes Limited Sels de benzodiazépine et leurs formes polymorphes à action brève
US9193730B2 (en) 2006-07-10 2015-11-24 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
US10472365B2 (en) 2006-07-10 2019-11-12 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
CN104059072B (zh) * 2006-07-10 2016-06-22 Paion英国有限公司 短效苯并二氮杂*盐及其多晶型
US9777007B2 (en) 2006-07-10 2017-10-03 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
US9914738B2 (en) 2006-07-10 2018-03-13 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms
WO2008091169A2 (fr) 2007-01-22 2008-07-31 Tomasz Kozluk Nobilus Ent Procédé de préparation de la forme polymorphe i d'olanzapine sensiblement pure
WO2008091169A3 (fr) * 2007-01-22 2009-02-05 Tomasz Kozluk Nobilus Ent Procédé de préparation de la forme polymorphe i d'olanzapine sensiblement pure
US10195210B2 (en) 2010-11-08 2019-02-05 Paion Uk Ltd. Dosing regimen for sedation with CNS 7056 (Remimazolam)
US10342800B2 (en) 2010-11-08 2019-07-09 Paion Uk Ltd. Dosing regimen for sedation with CNS 7056 (Remimazolam)
US12201637B2 (en) 2010-11-08 2025-01-21 Paion Uk Ltd. Dosing regimen for sedation with CNS 7056 (Remimazolam)
US10414749B2 (en) 2013-03-04 2019-09-17 Paion Uk Limited Process for preparing 3-[(S)-7-bromo-2-((2-oxopropyl)amino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionic acid methyl ester
EP4146656A4 (fr) * 2020-05-05 2024-06-26 Syneurx International (Taiwan) Corp. Sels de neuroceutiques et leurs utilisations

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SI21850A (sl) 2006-02-28
WO2006010620A3 (fr) 2006-06-08

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