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WO2019179920A1 - Procédé de fabrication de pimavansérine - Google Patents

Procédé de fabrication de pimavansérine Download PDF

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Publication number
WO2019179920A1
WO2019179920A1 PCT/EP2019/056668 EP2019056668W WO2019179920A1 WO 2019179920 A1 WO2019179920 A1 WO 2019179920A1 EP 2019056668 W EP2019056668 W EP 2019056668W WO 2019179920 A1 WO2019179920 A1 WO 2019179920A1
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WO
WIPO (PCT)
Prior art keywords
process according
isobutoxyphenyl
methylpiperidin
pimavanserin
base
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2019/056668
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English (en)
Inventor
Nicola ANTOLINI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lundbeck Pharmaceuticals Italy SpA
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Lundbeck Pharmaceuticals Italy SpA
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Filing date
Publication date
Application filed by Lundbeck Pharmaceuticals Italy SpA filed Critical Lundbeck Pharmaceuticals Italy SpA
Publication of WO2019179920A1 publication Critical patent/WO2019179920A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

Definitions

  • the present invention relates to a new process for manufacturing 1-(4-fluorobenzyl)-3-(4-iso- butoxyphenyl)-1-(1-methylpiperidin-4-yl)urea, with the INN name pimavanserin, and its hemi- tartrate salt.
  • Pimavanserin is an atypical antipsychotic indicated for the treatment of hallucinations and de- lusions associated with Parkinson’s disease psychosis. Pimavanserin is marketed by Acadia Pharmaceuticals under the brand name Nuplazid, as the hemitartrate salt.
  • Pimavanserin can be obtained by various synthetic routes, as disclosed by Acadia Pharma- ceuticals in e.g. WO 2004/064738, WO 2006/037043, WO 2007/133802 and WO
  • the present invention relates to an improved process for producing pimavanserin, 1-(4-fluoro- benzyl)-3-(4-isobutoxyphenyl)-1 -(1 -methylpiperidin-4-yl)urea.
  • the invention relates to a process for manufacturing of pimavanserin, said pro- cess comprising the following step,
  • the invention relates to pimavanserin or pimavanserin hemitartrate di- rectly obtained by the process of the invention.
  • the invention relates to a pharmaceutical composition comprising pimavanserin or pimavanserin hemitartrate di- rectly obtained by the process of the invention.
  • pimavanserin without specification of any particular salt form is intended to include any form of the compound, such as the free base and pharmaceu- tically acceptable salts.
  • the free base and pharmaceutically acceptable salts include anhy- drous forms and solvated forms such as hydrates.
  • the anhydrous forms and the solvates in- clude amorphous and crystalline forms.
  • pimavanserin is in the form of the hemitartrate salt and is then denoted“pimavanserin hemitartrate”.
  • the term“purity” indicates the percentage by area of the product deter- mined by a chromatographic method, such as gas liquid chromatography (GC) or high perfor- mance liquid chromatography (HPLC).
  • a chromatographic method such as gas liquid chromatography (GC) or high perfor- mance liquid chromatography (HPLC).
  • the term "therapeutically effective amount" of a compound means an amount sufficient to alleviate, arrest, partly arrest, remove or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the admin- istration of said compound.
  • An amount adequate to accomplish this is defined as “therapeuti- cally effective amount”.
  • Effective amounts for each purpose will depend e.g. on the severity of the disease or injury as well as the weight and general state of the subject. It will be under- stood that determining an appropriate dosage may be achieved using routine experimenta- tion, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.
  • “treatment” or“treating” is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partly arresting, removing or delaying progress of the clinical manifestation of the disease.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • the inventors have found an improved process for producing pimavanserin, 1-(4-fluoroben- zyl)-3-(4-isobutoxyphenyl)-1-(1-methylpiperidin-4-yl)urea.
  • the process has been improved compared to the process very briefly suggested in WO 2004/064738 and more detailed in US 2008/0280886.
  • the invention relates to a process for manufacturing of pimavanserin, said pro- cess comprising the following step,
  • Said process step is a combination of steps 4 and 5 illustrated in scheme 1 below:
  • steps 4 and 5 occurs without isolation of 1-isobutoxy-4-(isocy- anatomethyl)benzene.
  • Steps 1 , 2 and 3 are further embodiments of the invention, exemplifying processes for prepa- ration of 2-(4-isobutoxyphenyl)acetic acid and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine.
  • N-(4-fluorobenzyl)-1-methylpiperidin-4-amine is prepared by reacting 4-fluoroben- zylamine and N-methylpiperidin-4-one under catalytic hydrogenation.
  • WO 2004/064738 suggests the use of the toxic sodium cyanoborohydride for the reduction. This step has been exemplified in WO 2009/039461 which relates to the synthesis of pima- vanserin metabolite derivatives.
  • WO 2009/039461 N-(4-fluorobenzyl)-1-methylpiperidin-4- amine is obtained in a yield of 50%.
  • WO 2006/037043 and US 2008/0280886 disclose the use of triacetoxy borohydride as reduc- tive agent obtaining N-(4-fluorobenzyl)-1-methylpiperidin-4-amine in yields of 92% and >82%.
  • WO 2007/133802 discloses reduction using a palladium catalyst obtaining a yield of 78.1%.
  • the present inventors have performed the reduction by catalytic hydrogenation using Pd/C as catalyst.
  • Crude N-(4-fluorobenzyl)-1-methylpiperidin-4-amine was purified through formation of the hydrochloride salt followed by base liberation using the methods known to the person skilled in the art.
  • N-(4-fluorobenzyl)-1-methylpiperidin-4-amine was thus obtained in high yields and very high purities without the need of fractional distillation and recovery of product from impure fractions as described in WO 2007/133802.
  • step 2) methyl 2-(4-hydroxyphenyl)acetate is reacted with an excess of isobutyl bromide under Williamson ether synthesis conditions to obtain methyl 2-(4-isobutoxyphenyl)acetate.
  • the reaction takes place in a polar solvent like ethanol, methanol, dimethylformamide (DMF) or dimethylsulfoxide (DMSO), or mixtures thereof; in presence of an organic or inorganic base, such as for example K2CO 3 .
  • a polar solvent like ethanol, methanol, dimethylformamide (DMF) or dimethylsulfoxide (DMSO), or mixtures thereof; in presence of an organic or inorganic base, such as for example K2CO 3 .
  • the reaction proceeds over several hours to obtain methyl 2-(4-isobutoxyphenyl)acetate in a high yield and purity.
  • Step 3 involves hydrolysis of the ester intermediate methyl 2-(4-isobutoxyphenyl)ac- etate to its corresponding acid.
  • the hydrolysis is performed in the presence of a strong base such as for example NaOH.
  • Steps 4-5 The inventors found that steps 4 and 5 can conveniently be combined avoiding isolation of the unstable 1-isobutoxy-4-(isocyanatomethyl)benzene.
  • 2-(4-isobutoxyphenyl)acetic acid and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine are dis solved in an organic solvent such as for example a solvent selected from the group consisting of toluene, xylene, heptane, acetonitrile, isopropylacetate, tetrahydrofuran (THF), 2-methyltet- rahydrofuran (MTHF), 1 ,4-dioxane, cyclopentyl methyl ether, dichloromethane, dimethylfor- mamide, dimethylacetamide, N-methylpyrrolidinone, N-ethylpyrrolidinone and dimethylsulfox- ide; and the mixture is heated.
  • an organic solvent such as for example a solvent selected from the group consisting of toluene, xylene, heptane, acetonitrile, isopropylacetate, tetrahydrofur
  • DPPA Diphenylphosphoryl azide
  • said reaction takes place in the presence of a base.
  • said base is an or- ganic base selected from N,N- diisopropylethylamine (DIPEA), N-methylmorpholine (NMM) and triethylamine (TEA).
  • DIPEA N,N- diisopropylethylamine
  • NMM N-methylmorpholine
  • TAA triethylamine
  • said base is an inorganic base.
  • WO 2004/064738 and WO 2009/039461 disclose preparation of 1-isobutoxy-4-(isocy- anatomethyl)benzene by reacting 2-(4-isobutoxyphenyl)acetic acid with 8,8-bisdimethyla- mino-naphthalene (Proton SpongeTM). After isolation 1-isobutoxy-4-(isocyanatomethyl)ben- zene was used for further processing to Pimavanserin (WO 2004/064738) or a related metab- olite derivative in a yield of 91% (WO 2009/039461 ).
  • steps 4) and 5) can be performed without the isolation of 1- isobutoxy-4-(isocyanatomethyl)benzene
  • the inventors obtained crude pimavanserin in a yield as high as 99% starting directly from 2-(4-isobutoxyphenyl)acetic acid and N-(4-fluoroben- zyl)-1 -methylpiperidin-4-amine.
  • Step 6 In this optional step, crude pimavanserin is mixed with ethanol and tartaric acid and precipitated as the hemitartrate.
  • the inventors also found that the main impurity of the final reaction, namely N-(4-fluoroben- zyl)-2-(4-isobutoxyphenyl)-N-(1-methylpiperidiin-4-yl)acetamide and depicted below, surpris- ingly remains in solution and does not precipitate as a tartrate salt despite the structural simi- larity with Pimavanserin.
  • Pimavanserin was obtained as a hemitartrate salt in a very high purity such as a purity above 99%.
  • Each of the intermediates obtained according to process steps 1 , 2 and 3 can be used for fur- ther processing in isolated form or without being isolated, and in all purities.
  • one or more of said intermediates have been isolated before fur- ther processing, such that for example N-(4-fluorobenzyl)-1-methylpiperidin-4-amine obtained from step 1 ) has been isolated before it is used for the reaction in steps 4-5).
  • one or more said intermediates have been isolated and purified be- fore further processing, such that for example N-4-fluorobenzyl)-1-methylpiperidin-4-amine obtained from step 1 ) has been isolated and purified before it is used for the reaction in steps
  • one or more of said intermediates are used for further processing in a purity of at least 90%, such as at least 95%, such as at least 97%, such as at least 98% such as at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8 or 99.9%. Purity is measured by GC or HPLC as described in the experimental section.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Pimavanserin obtained by the process of the invention.
  • the pharmaceutical composition may further corn- prise at least one pharmaceutically acceptable excipient, carrier and/or diluent, and may be in a solid dosage form, such as a tablet, for oral administration.
  • Solid preparations such as tablets, may be prepared by mixing the active in- gredients with an ordinary carrier, such as an adjuvant and/or diluent, and subsequently corn- pressing the mixture in a tableting machine.
  • an adjuvant and/or dilu- ents include: corn starch, lactose, talcum, magnesium stearate, gelatin, lactose, gums, and the like.
  • compositions of the invention thus typically comprise an effective amount of Pimavanserin and one or more pharmaceutically acceptable carriers.
  • Pimavanserin obtained according to the present invention may be administered by any suita- ble administration route, e.g. orally or parenterally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solu- tions or dispersions for injection.
  • the pharmaceutical composition will corn- prise Pimavanserin in a therapeutically effective amount.
  • the amount of Pimavanserin in a pharmaceutical composition in a unit dosage form is from 1 mg to 50 mg, such as from 5 mg to 25 mg, such as for example 5, 6, 7, 8, 9,
  • Pimavanserin has been approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. It is furthermore being investigated for the treatment of symptoms within Alzheimer’s Disease (AD), Schizophrenia and Major Depressive Disorder. It is envisaged that Pimavanserin obtained by the process of the invention may be used in the treatment of CNS disorders such as Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Schizophrenia and Major Depressive Disorder. In particular, Pimavanserin obtained by the process of the invention may be used in the treatment of hallucinations and delusions associ- ated with Parkinson’s disease psychosis.
  • CNS disorders such as Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Schizophrenia and Major Depressive Disorder.
  • Pimavanserin obtained by the process of the invention may be used in the treatment of hallucinations and delusions associ- ated with Parkinson’s disease psychosis.
  • the first embodiment is denoted E1
  • the second embodiment is denoted E2 and so forth.
  • a process for manufacturing of pimavanserin comprising the following step:
  • said base is selected from the group consisting of organic bases such as triethylamine (TEA), N-methylmorpholine (NMM) and N,N-diisopropylethylamine (DIPEA); or wherein said base is selected from the group consisting of inorganic bases.
  • organic bases such as triethylamine (TEA), N-methylmorpholine (NMM) and N,N-diisopropylethylamine (DIPEA)
  • DIPEA N,N-diisopropylethylamine
  • a pharmaceutical composition comprising pimavanserin obtained by the process ac- cording to any of embodiments 1 -18 or comprising pimavanserin hemitartrate obtained by the process according to any of embodiments 19-22.
  • a CNS disorder such as Parkinson’s Disease (PD), Alzheimer’s Dis- ease (AD), Schizophrenia or Major Depressive Disorder
  • a method for the treatment of a CNS disorder such as Parkinson’s Disease (PD), Alz- heimer’s Disease (AD), Schizophrenia or Major Depressive Disorder; such as a method for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, which method comprises the administration of a therapeutically effective amount of pimavan- serin obtained by the process according to any of embodiments 1 -18 or pimavanserin hemi- tartrate obtained by the process according to any of embodiments 19-22.
  • a CNS disorder such as Parkinson’s Disease (PD), Alz- heimer’s Disease (AD), Schizophrenia or Major Depressive Disorder
  • PD Parkinson’s Disease
  • AD Alz- heimer’s Disease
  • Schizophrenia or Major Depressive Disorder such as a method for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, which method comprises the administration of a therapeutically effective amount of pimavan- serin obtained by the process according to
  • pimavanserin obtained by the process according to any of embodiments 1 -18 or pimavanserin hemitartrate obtained by the process according to any of embodiments 19- 22, in the manufacture of a medicament for the treatment of a CNS disorder such as Parkin- son’s Disease (PD), Alzheimer’s Disease (AD), Schizophrenia or Major Depressive Disorder; such as for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.
  • a CNS disorder such as Parkin- son’s Disease (PD), Alzheimer’s Disease (AD), Schizophrenia or Major Depressive Disorder
  • PD Parkin- son’s Disease
  • AD Alzheimer’s Disease
  • Schizophrenia or Major Depressive Disorder
  • Carrier flow helium (1.0 ml/min)
  • Example 1 formation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine from 4-fluorobenzyla- mine and N-methylpiperidin-4-one.
  • Example 1a formation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine from 4-fluorobenzyla- mine and N-methylpiperidin-4-one.
  • the crude product was dissolved in isopropanol (I PA) (1500 ml.) and HCI 37% (1 12 g) was added obtaining a suspension.
  • the product was isolated by filtration and charged in a re- actor with water and toluene. NaOH 30% was added dropwise (126 ml_). The phases were separated and the organic phase was concentrated to residue under vacuum obtaining 1 1 1 g (89.3% yield) of an oil with a purity of 99.6% (area, GC).
  • Example 2 formation of methyl 2-(4-isobutoxyphenyl)acetate from methyl 2-(4-hydroxy- phenvDacetate and isobutyl bromide.
  • a reactor was charged with methyl 2-(4-hydroxyphenyl)acetate (10.0 g), isobutyl bromide (16.5 g), potassium carbonate (16.6 g) and DMF (100 ml_). The mixture was heated at 145 °C and stirred for 24 hours. The mixture was concentrated to residue under vacuum and toluene (100 ml.) and water (100 ml.) were added. The phases were separated and the organic phase was washed with water and concentrated to residue under vacuum obtaining 11.7 g of oil (88% yield) with a purity of 94.7% (area, HPLC).
  • Example 3 formation of 2-(4-isobutoxyphenyl)acetic acid from methyl 2-(4-isobutoxy- phenvDacetate.
  • Example 4 formation of pimavanserin from 2-(4-isobutoxyphenyl)acetic acid and N-(4-fluoro- benzyl)-1-methylpiperidin-4-amine.
  • Example 5 Precipitation of pimavanserin hemitartrate.
  • a reactor was charged with crude Pimavanserin (110.0 g) obtained from Example 4a and ab- solute ethanol (770 ml_). The mixture was heated to 50°C obtaining a solution. Tartaric acid (19.3 g) was dissolved in absolute ethanol (80 ml.) and the solution was added dropwise into the reactor. The mixture was cooled to 20°C over a 17 h period obtaining a suspension. The solid was isolated by filtration and dried under vacuum obtaining 104.6 g (81 % yield) of the compound as a crystalline powder with a purity of 99.5% (area, HPLC).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un nouveau procédé de fabrication de 1-(4-fluorobenzyl)-3-(4-isobutoxyphényle)-1-(1-méthylpipéridin-4-yl)urée, son nom INN étant la pimavansérine, et son sel hémitartrate. Ledit procédé comprend l'étape suivante : la mise en contact de l'acide 2-(4-isobutoxyphényl)acétique avec de la N-(4-fluorobenzyl)-1-méthylpipéridin-4-amine en présence d'une base et d'azide de diphénylphosphoryle (DPPA) pour obtenir la pimavansérine.
PCT/EP2019/056668 2018-03-19 2019-03-18 Procédé de fabrication de pimavansérine Ceased WO2019179920A1 (fr)

Applications Claiming Priority (2)

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IT102018000003736A IT201800003736A1 (it) 2018-03-19 2018-03-19 Processo per la produzione di Pimavanserin
IT102018000003736 2018-03-19

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WO2019179920A1 true WO2019179920A1 (fr) 2019-09-26

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004064738A2 (fr) 2003-01-16 2004-08-05 Acadia Pharmaceuticals Inc. Agonistes inverses selectifs pour le recepteur de la serotonine 2a/2c utilises comme agents therapeutiques contre les maladies neurodegeneratives
WO2006037043A1 (fr) 2004-09-27 2006-04-06 Acadia Pharmaceuticals Inc. Synthese de n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide, tartrate de ce compose et ses formes cristallines
WO2007124136A1 (fr) * 2006-04-19 2007-11-01 Acadia Pharmaceuticals, Inc. Utilisation de 4-amino-piperidines pour le traitement des troubles du sommeil
WO2007133802A2 (fr) 2006-05-15 2007-11-22 Acadia Pharmaceuticals Inc. Formules pharmaceutiques de pimavansérine
US20080280886A1 (en) 2007-05-08 2008-11-13 Auspex Pharmaceuticals, Inc. Substituted ureas
WO2008144326A2 (fr) 2007-05-15 2008-11-27 Acadia Pharmaceuticals Inc. Synthèse de n-(4-fluorobenzyl)-n-(l-méthylpypéridine-4-yl)-n'-(4-2-méthylpropyloxy)phénylméthyl)carbamide et son sel de tartrate et des formes cristallines
WO2009039461A2 (fr) 2007-09-21 2009-03-26 Acadia Pharmaceuticals, Inc. Dérivés de pipéridine n-substitués en tant qu'agents récepteurs de la sérotonine
WO2016141003A1 (fr) 2015-03-02 2016-09-09 Teva Pharmaceutical Industries Ltd. Procédés et intermédiaires pour la préparation de pimavansérine
WO2017036432A1 (fr) 2015-09-02 2017-03-09 Zentiva, K.S. Procédé de production de 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridin-4-yl)urée et de ses analogues deutérés ne contenant pas d'impuretés sous forme de dimères
WO2017054786A1 (fr) 2015-10-02 2017-04-06 Zentiva, K. S. Procédé de production du 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridine-4-yl)urée et de ses analogues deutérés

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004064738A2 (fr) 2003-01-16 2004-08-05 Acadia Pharmaceuticals Inc. Agonistes inverses selectifs pour le recepteur de la serotonine 2a/2c utilises comme agents therapeutiques contre les maladies neurodegeneratives
WO2006037043A1 (fr) 2004-09-27 2006-04-06 Acadia Pharmaceuticals Inc. Synthese de n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide, tartrate de ce compose et ses formes cristallines
WO2007124136A1 (fr) * 2006-04-19 2007-11-01 Acadia Pharmaceuticals, Inc. Utilisation de 4-amino-piperidines pour le traitement des troubles du sommeil
WO2007133802A2 (fr) 2006-05-15 2007-11-22 Acadia Pharmaceuticals Inc. Formules pharmaceutiques de pimavansérine
US20080280886A1 (en) 2007-05-08 2008-11-13 Auspex Pharmaceuticals, Inc. Substituted ureas
WO2008144326A2 (fr) 2007-05-15 2008-11-27 Acadia Pharmaceuticals Inc. Synthèse de n-(4-fluorobenzyl)-n-(l-méthylpypéridine-4-yl)-n'-(4-2-méthylpropyloxy)phénylméthyl)carbamide et son sel de tartrate et des formes cristallines
WO2009039461A2 (fr) 2007-09-21 2009-03-26 Acadia Pharmaceuticals, Inc. Dérivés de pipéridine n-substitués en tant qu'agents récepteurs de la sérotonine
WO2016141003A1 (fr) 2015-03-02 2016-09-09 Teva Pharmaceutical Industries Ltd. Procédés et intermédiaires pour la préparation de pimavansérine
WO2017036432A1 (fr) 2015-09-02 2017-03-09 Zentiva, K.S. Procédé de production de 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridin-4-yl)urée et de ses analogues deutérés ne contenant pas d'impuretés sous forme de dimères
WO2017054786A1 (fr) 2015-10-02 2017-04-06 Zentiva, K. S. Procédé de production du 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridine-4-yl)urée et de ses analogues deutérés

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS

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