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WO2024084379A1 - Nouveau procédé de préparation d'une dispersion solide amorphe de 1-3-[3- (4-chlorophenyl)propoxy] propyl} pipéridine, chlorhydrate avec de l'hydroxypropyl bêta-cyclodextrine (hpβcd) - Google Patents

Nouveau procédé de préparation d'une dispersion solide amorphe de 1-3-[3- (4-chlorophenyl)propoxy] propyl} pipéridine, chlorhydrate avec de l'hydroxypropyl bêta-cyclodextrine (hpβcd) Download PDF

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Publication number
WO2024084379A1
WO2024084379A1 PCT/IB2023/060444 IB2023060444W WO2024084379A1 WO 2024084379 A1 WO2024084379 A1 WO 2024084379A1 IB 2023060444 W IB2023060444 W IB 2023060444W WO 2024084379 A1 WO2024084379 A1 WO 2024084379A1
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WIPO (PCT)
Prior art keywords
pitolisant
acid
hydrochloride
cyclodextrin
base
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Ceased
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PCT/IB2023/060444
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English (en)
Inventor
Manik Reddy Pullagurla
Jagadeesh Babu Rangisetty
Bhaskar Reddy Pitta
Kiran Kumar Kothakonda
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Biophore India Pharmaceuticals Pvt Ltd
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Biophore India Pharmaceuticals Pvt Ltd
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Publication of WO2024084379A1 publication Critical patent/WO2024084379A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers

Definitions

  • the present invention relates to a novel process for the preparation of amorphous solid dispersion of l- ⁇ 3-[3-(4-chlorophenyl) propoxy] propyl ⁇ piperidine, hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).
  • hydrochloride commonly known as Pitolisant hydrochloride is represented by the following structural formula.
  • Pitolisant hydrochloride is designed and developed by Harmony Biosciences LLC. It is a histamine-3 (H3) receptor antagonist/inverse agonist which is used in the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy. Pitolisant hydrochloride is approved by USFDA in Aug 14, 2019, and is being marketed under the brand name WAKIX.
  • the present invention relates to a novel process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD (1).
  • amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) is having purity greater than 99.8%, preferably purity of at least 99.9%.
  • the present invention relates to a novel process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).
  • the compounds of formulae (8), (7) and (4) can be prepared in- situ and proceeds to next steps without further purification.
  • in another aspect of the present invention provides process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta- Cyclodextrin (HPpCD) (1), comprising the steps of: 1) reducing 3-(4-chlorophenyl) propanoic acid of formula (6) with reducing agent in the presence of Lewis acid to obtain 3-(4-chlorophenyl) propan- l-ol (5);
  • In another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta- Cyclodextrin (HPpCD) (1), comprising: i. reacting 3 -(4 -chlorophenyl) propyl methane sulfonate (4) with 3-(piperidin-l- yl) propan- l-ol (3) in the presence of base to obtain Pitolisant free base (2a); and ii. converting Pitolisant free base (2a) to provide Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).
  • HPpCD Hydroxypropyl beta- Cyclodextrin
  • Pitolisant free base (2) is having purity greater than 99.8%, preferably purity of at least 99.9%.
  • amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) is having purity greater than 99.8%, preferably purity of at least 99.9%.
  • Figure 1 X-Ray powder diffraction (XPRD) pattern of amorphous solid dispersion of Pitolisant hydrochloride with hydroxypropyl beta-cyclodextrin (HPpCD) (1) prepared by example 7.
  • XPRD X-Ray powder diffraction
  • the present invention relates to a process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).
  • HPpCD Hydroxypropyl beta-Cyclodextrin
  • Scheme-2 Scheme-2
  • step a) of the present invention proceeds with reacting 1-chloro- 4-(chloromethyl) benzene (10) with dimethyl malonate (9) to obtain dimethyl 2-(4- chlorobenzyl) malonate (8).
  • the reaction is carried out in the presence of suitable base in a suitable solvent.
  • the suitable base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide
  • the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
  • the compound of formula (8) of step a) can be prepared in-situ and proceeds to next steps without further purification.
  • step b) of the present invention proceeds with hydrolysing dimethyl 2-(4-chlorobenzyl) malonate (8) to obtain 2-(4-chlorobenzyl) malonic acid (7).
  • the reaction is carried out in present of suitable base in a suitable solvent.
  • the suitable base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and the like
  • the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
  • the compound of formula (7) of step b) can be prepared in-situ and proceeds to next steps without further purification.
  • step c) of the present invention proceeds with decarboxylating 2-(4-chlorobenzyl) malonic acid (7) to obtain 3-(4-chlorophenyl) propanoic acid (6).
  • the reaction is carried out in presence of a suitable acid selected from hydrochloric acid or sulfuric acid, optionally purifying 3-(4-chlorophenyl) propanoic acid (6), wherein the purification process comprises. i. dissolving 3-(4-chlorophenyl) propanoic acid (6) in a suitable solvent. ii. adding an anti-solvent; and iii. isolating 3-(4-chlorophenyl) propanoic acid (6).
  • step c) wherein the suitable solvent used in step i) is selected from “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; and the anti-solvent used in step ii) is selected from “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, and the like.
  • hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like
  • step d) of the present invention proceeds with reducing 3-(4- chlorophenyl) propanoic acid of formula (6) with a suitable reducing agent to obtain 3-(4-chlorophenyl) propan-l-ol of formula (5).
  • the reaction is carried out in the presence of a suitable Lewis acid in a suitable solvent.
  • the suitable reducing agent is selected from DIBAL, sodium borohydride, potassium borohydride, lithium trisec -butyl borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate (Vitride), diisobutylaluminium hydride, lithium aluminum hydride
  • the suitable Lewis acid is selected from aluminum chloride (A1CL), boron trifluoride etherate (BF3:Et2O), Cone. Sulfuric acid (Cone. H2SO4) etc.
  • the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
  • step e) of the present invention proceeds with mesylating 3-(4- chlorophenyl) propan-l-ol of formula (5) with methane sulfonyl chloride to obtain 3-(4-chlorophenyl) propyl methane sulfonate (4).
  • the reaction is carried out in the presence of organic base in a suitable solvent.
  • the organic base is selected from triethyl amine, methyl amine, ethylamine, isopropyl amine, diisopropylamino, diisopropylethylamine, and the like
  • the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
  • step f) of the present invention proceeds with reacting 3-(4- chlorophenyl) propyl methane sulfonate (4) with 3-(piperidin-l-yl) propan-l-ol (3) to obtain crude Pitolisant free base (2a).
  • the reaction is carried out in the presence of suitable base in a suitable solvent.
  • the suitable base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
  • step g) of the present invention proceeds with purifying crude Pitolisant free base (2a) by acid base treatment to obtain pure Pitolisant free base (2).
  • the process involves reacting crude Pitolisant free base (2a) with a suitable acid to obtain acid addition salt of Pitolisant (2b).
  • the acid employed for preparing Pitolisant acid addition salts includes but not limited to formic acid, acetic acid, oxalic acid, propanoic acid, maleic acid, citric acid, phthalic acid, toluene sulfonic acid, naphthalene sulphonic acid, methansulfonic acid, benzenesulfonic acid and the like.
  • the Pitolisant acid addition salt (2b) can be neutralized to give highly pure Pitolisant free base (2).
  • the neutralization of acid addition salt carried out in presence of suitable base at a temperature of about 25 to 35 °C.
  • suitable base that can be used for conversion of Pitolisant acid addition salt (2b) to Pitolisant free base (2) can be inorganic base.
  • Inorganic base includes but are not limited to alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, and the like, and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
  • alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like
  • alkali metal carbonates such as sodium carbonate, potassium carbonate and the like
  • alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, and the like
  • the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents,
  • step h) of the present invention proceeds with converting pure Pitolisant free base (2) to amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) without isolating Pitolisant hydrochloride.
  • HPpCD Hydroxypropyl beta-Cyclodextrin
  • step h) of the present invention provides process for the preparation of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) from pure Pitolisant free base (2) without isolating Pitolisant hydrochloride, comprising the steps of:
  • the suitable solvent used in Step A is “polar solvents” such as water.
  • Scheme 3 comprising: dehydrochlorination of piperidine with 3 -chloropropanol to obtain 3- (piperidin-l-yl) propan-l-ol (3); the reaction is carried out in the presence of base, potassium iodide in a suitable solvent
  • the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate and the like
  • the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
  • Pitolisant free base (2) obtained by the above process may be having purity greater than 99.8%, preferably purity of at least 99.9%.
  • Amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta- Cyclodextrin (HPpCD) (1) obtained by the above process may be is having purity greater than 99.8%, preferably purity of at least 99.9%.
  • Substantially pure Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextnn (HPpCD) (1) obtained by the above process is having total impurities not more than 1.0% and each of impurity-A, impurity-B, impurity-C, and impurity-D is not more than 0.15% (w/w), preferably not more than 0.05% (w/w); and impurity-E is not more than 2.0% (w/w), more preferably not more than 0.5% (w/w).
  • Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) obtained according to the present invention has a water content not more than 10.0%, preferably not more than 5%. More preferably not more than 3%.
  • PXRD powdered x-ray diffractogram
  • suitable solvent refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3 -dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene 5 glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate
  • Example-1 Process for the preparation of 3-(piperidin-l-yl) propan-l-ol (3) 100 g of piperidine, 500 ml of toluene, 260 g of potassium carbonate and 19 g of potassium iodide were taken at 25-30 °C. 116 g of 3-chloropropan-l-ol was added to the reaction mass. The reaction mass temperature was raised to 40-45 °C and stirred for 30-40 minutes. The reaction mass temperature was raised to 108-112°C and stirred for 14-16 hours. After completion of the reaction, the reaction mass was cooled to 25-30°C. The reaction mass was filtered and washed with toluene. The filtrate was distilled off under vacuum to get crude as oily liquid. The crude was purified by fractional distillation to get the titled compound. Yield: 80%; Purity: 99.95%
  • Example-2 Process for the preparation of 3-(4-chlorophenyl) propanoic acid (6):
  • the reaction temperature was raised to 110-115 °C and stirred for 12-14 hours. After completion of the reaction, the reaction mass was cooled to 25-30 °C. 200ml of toluene was added to the reaction mass and stirred for 10-15 minutes at 25-30 °C. Both the layers were separated. The aqueous layer pH was adjusted from 1.0 to 1.5 with cone, hydrochloric acid. The reaction temperature was raised to 140-145 °C and stirred for 14-15 hours. The reaction mass was cooled to 25-30 °C. Filtered the solid and washed with water to obtain crude 3-(4-chlorophenyl) propanoic acid (6). To this crude compound, 500 ml of water was added at 25-30 °C.
  • the reaction temperature was raised to 110-115 °C and stirred for 1-2 hours.
  • the reaction mass was cooled to 25-30°C and stirred. Filtered the solid and dried to obtain dry crude 3-(4-chlorophenyl) propanoic acid (6).
  • To this 500 ml of hexane was added at 25-30 °C and the reaction temperature raised up to 60-65 °C then, 130 ml of ethyl acetate was added and stirred.
  • the reaction mass was cooled to room temperature and cooled to 0-5°C for 1-1.5 hours. Filtered the solid and washed with hexane. The obtained solid was dried at 40-45 °C to get the titled compound.
  • Example-3 Process for the preparation of 3-(4-chlorophenyl) propan-l-ol (5): 120 mL of tetrahydrofuran was added to 30 g of sodium borohydride at 25-30 °C and stirred for 20-30 minutes. To this 100 ml of Boron trifluoride etherate (BF3.Et2O) was added slowly to the reaction mass at below 30 °C and stirred for 20-30 minutes. Then the reaction mass was cooled 0-5 °C.
  • BF3.Et2O Boron trifluoride etherate
  • Example-4 Process for the preparation of 3-(4-chlorophenyl) propyl methane sulfonate (4):
  • reaction mass temperature was raised to 50-55 °C and stirred for 30-40 minutes.
  • 13.55 g of sodium tert-pentoxide was added to the reaction mass at 50-55 °C and stirred for 1 hour.
  • 5.35 g of sodium tert-pentoxide was added to the reaction mass and stirred for 2-3 hours.
  • 350 ml of 10% ammonium chloride solution was added to the reaction mass at 0-5 °C and stirred for 15-20 minutes.
  • the reaction mass temperature was raised to 25-30°C. Both the layers were separated. The aqueous layer was re-extracted with 70 ml of methyl tert-butyl ether to obtain crude.
  • the obtained crude was dissolved in 200 ml of methyl tert-butyl ether and cooled to 0-5 °C.
  • the pH of reaction mass was adjusted to 1.0-2.0 with 2N hydrochloric acid and stirred for 10-15 minutes. Both the layers were separated.
  • the aqueous layer was basified with 3N sodium hydroxide to adjust the pH from 11.0-12.0 and stirred for 10-15 minutes.
  • the organic layer was taken and 10.0 g of neutral carbon into the reaction mass was added.
  • the reaction mass was stirred for 10-15 minutes.
  • the reaction temperature was raised to 50-55°C and stirred for 1 h.
  • the reaction mass cooled to room temperature, then filtered the reaction mass and washed with 35 mL of methyl tert-butyl ether.
  • Example-6 Process for the purification of Pitolisant (2)
  • Example-7 Process for the preparation of solid dispersions of Pitolisant hydrochloride (1) with Hydroxypropyl beta- Cyclodextrin (HPpCD) 100 g of Pitolisant free base (2) and 500 ml of water was taken at room temperature. The reaction mass was cooled 0-5 °C. To this 25 ml of concentrated Hydrochloric acid was added to the reaction mass at 0-5 °C then stirred for 15-20 minutes. The pH of the reaction mass was adjusted to 3.2 to 4.0 by slowly addition of Hydrochloric acid. The reaction mass temperature was raised to 25-30°C. 300 g of Hydroxypropyl P-cyclodextrin (HPpCD) was added and stirred for 20-30 minutes. The reaction mass was passed through 0.2-micron filter. The filtrate was loaded into the freeze dryer and dried to get a title compound. Yield: 92%; Purity: >99.9%

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Abstract

La présente invention concerne un nouveau procédé de préparation d'une dispersion solide amorphe de 1-3-[3- (4-chlorophényl) propoxy] propyl} pipéridine, de chlorhydrate avec de l'Hydroxypropyl-bêta-cyclodextrine (HPβCD) (1). La présente invention concerne en outre la purification de pitolisant (2). Formule (I)
PCT/IB2023/060444 2022-10-17 2023-10-17 Nouveau procédé de préparation d'une dispersion solide amorphe de 1-3-[3- (4-chlorophenyl)propoxy] propyl} pipéridine, chlorhydrate avec de l'hydroxypropyl bêta-cyclodextrine (hpβcd) Ceased WO2024084379A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202241059154 2022-10-17
IN202241059154 2022-10-17

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WO2024084379A1 true WO2024084379A1 (fr) 2024-04-25

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PCT/IB2023/060444 Ceased WO2024084379A1 (fr) 2022-10-17 2023-10-17 Nouveau procédé de préparation d'une dispersion solide amorphe de 1-3-[3- (4-chlorophenyl)propoxy] propyl} pipéridine, chlorhydrate avec de l'hydroxypropyl bêta-cyclodextrine (hpβcd)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4457219A4 (fr) * 2021-12-29 2025-12-10 Biophore India Pharmaceuticals Pvt Ltd Formes solides de chlorhydrate de 1-3-[3-(4-chlorophényl) propoxy] propyl} pipéridine et leur procédé de préparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006084833A1 (fr) * 2005-02-10 2006-08-17 Bioprojet Sel de monohydrochlorure de 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine
CN103435575A (zh) * 2013-08-06 2013-12-11 中国人民解放军军事医学科学院毒物药物研究所 1-（ 3-（ 3-（ 4-氯苯基）丙氧基）丙基）哌啶盐酸盐的制备方法
EP3239138A1 (fr) * 2016-04-25 2017-11-01 Sandoz Ag Sel de fumarate d'hydrogène de 1-[3-[3-(4-chlorophényl)propoxy]propyl]pipéridine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006084833A1 (fr) * 2005-02-10 2006-08-17 Bioprojet Sel de monohydrochlorure de 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine
CN103435575A (zh) * 2013-08-06 2013-12-11 中国人民解放军军事医学科学院毒物药物研究所 1-（ 3-（ 3-（ 4-氯苯基）丙氧基）丙基）哌啶盐酸盐的制备方法
EP3239138A1 (fr) * 2016-04-25 2017-11-01 Sandoz Ag Sel de fumarate d'hydrogène de 1-[3-[3-(4-chlorophényl)propoxy]propyl]pipéridine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4457219A4 (fr) * 2021-12-29 2025-12-10 Biophore India Pharmaceuticals Pvt Ltd Formes solides de chlorhydrate de 1-3-[3-(4-chlorophényl) propoxy] propyl} pipéridine et leur procédé de préparation

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