WO2018092151A1 - Procédé de préparation de l'acide 2- (e)-n-hydroxy-3-[4- [[ [2- (2-méthyl -1 h-indol-3-yl) éthyl] amino] méthyl] phényl]-2-propénamide 2-hydroxypropanoïque (1 : 1) et ses polymorphes - Google Patents

Procédé de préparation de l'acide 2- (e)-n-hydroxy-3-[4- [[ [2- (2-méthyl -1 h-indol-3-yl) éthyl] amino] méthyl] phényl]-2-propénamide 2-hydroxypropanoïque (1 : 1) et ses polymorphes Download PDF

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WO2018092151A1
WO2018092151A1 PCT/IN2017/000132 IN2017000132W WO2018092151A1 WO 2018092151 A1 WO2018092151 A1 WO 2018092151A1 IN 2017000132 W IN2017000132 W IN 2017000132W WO 2018092151 A1 WO2018092151 A1 WO 2018092151A1
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methyl
formula
compound
indol
ethyl
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PCT/IN2017/000132
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English (en)
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Sagyam RAJESHWAR REDDY
Ghojala Venkat Reddy
Boge RAJESHAM
Mallam VENKATAIAH
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Msn Laboratories Private Limited, R&D Center
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Publication of WO2018092151A1 publication Critical patent/WO2018092151A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • A61K9/146—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 with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/08—Lactic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to novel crystalline and amorphous forms of 2-(E)-N- hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-y l)ethyl]amino]methyl]phenyl]-2-propenamide 2- hydroxypropanoic acid ( 1 : 1 ) and its process for the preparation.
  • the present invention also relates to solid dispersions of 2-(E)-N-hydroxy-3-(4- ([[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide 2-hydroxypropano ic acid ( 1 : 1 ) and its preparation thereof.
  • the present invention also relates to improved process for the preparation of 2- (E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl)-2-propen amide 2-hydroxypropanoic acid ( 1 : 1 ) .
  • Panobinostat lactate is marketed in US by Novartis under the brand name of "Farydak" for the treatment of various cancers. It is a hydroxamic acid and acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor).
  • US6552065 B2 (hereinafter referred as US'065) first discloses the Panobinostat and its process for the preparation thereof.
  • US201 101 12308 A l discloses formation of amorphous form of calcium, zinc, potassium, hemi fumarate, oxalate, hemi maleate, mesylate and phosphate salts of Panobinostat.
  • US7989494 B2 relates to crystalline forms of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide and its salts.
  • it discloses calcium, potassium, zinc, phosphate, tartrate, mesylate, acetate, benzoate, hemi malate and lactate salts of Panobinostat.
  • Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
  • Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • the first aspect of the present invention is to provide amorphous form of 2-(E)-N- hydroxy-3-[4-[[[2-(2-methyl- 1 H-indolO-yl)ethyl]amino]methyl]phenyl]-2-propenam lactate compound of formula- l a and process for its preparation.
  • the second aspect of the present invention is to provide amorphous solid dispersion comprising of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-y l)ethyl]amino]methyl] phenyl]-2-propenamide lactate compound of formula- l a and at least one pharmaceutically acceptable excipient and process for its preparation.
  • the third aspect of the present invention is to provide novel crystalline form of 2-(E)- N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide of compound formula- 1 and process for its preparation.
  • the fourth aspect of the present invention is to provide amorphous form of 2-(E)-N- hydroxy-3-(4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide of compound formula- 1 and process for its preparation.
  • the fifth aspect of the present invention is to provide novel crystalline form of 2-(E)- N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide lactate compound of formula- 1 a and process for its preparation.
  • the sixth aspect of the present invention is to provide an improved process for the preparation of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-y l)ethyl]amino]methyl] phenyl]-2-propenamide lactate compound of formula- l a.
  • the seventh aspect of the present invention is to provide novel acid addition salts of (E)-methyl 3-(4-(((2-(2-methyl- 1 H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylate compound of formula-5 and its process for the preparation.
  • the eighth aspect of the present invention is to provide novel crystalline form of 2- (E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propen amide hydrobromide salt compound of formula- l b, herein after designated as crystalline Form-M3.
  • Figure-1 Illustrates the PXRD pattern of amorphous form of 2-(E)-N-hydroxy-3-[4- [[[2-(2- methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide lactate compound of formula- 1 a obtained according to example- 1 .
  • Figure-2 Illustrates the PXRD pattern of amorphous form of 2-(E)-N-hydroxy-3-[4- [[[2-(2- methyl- 1 H-indol-3-yi)ethyl]amino]methyl)phenyl]-2-propenamide lactate compound of formula- l a obtained according to example-2.
  • Figure-3 Illustrates the PXRD pattern of amorphous solid dispersion comprising 2-(E)-N- hydroxy-3-(4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide lactate compound of formula- l a and PVP-K-30.
  • Figure-4 Illustrates the PXRD pattern of amorphous solid dispersion comprising 2-(E)-N- hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide lactate compound of formula- l a and HPMC.
  • Figure-5 Illustrates the PXRD pattern of amorphous solid dispersion comprising 2-(E)-N- hydroxy-3-(4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino)methyl]phenyl)-2-propenamide compound of formula- l a and HPC.
  • Figure-6 Illustrates the PXRD pattern of amorphous solid dispersion comprising 2-(E)-N- hydroxy-3-[4-[((2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide compound of formula- 1 a and HPMC-AS( 1 : 1 ).
  • Figure-7 Illustrates the PXRD pattern of novel crystalline Form-M of 2-(E)-N-hydroxy-3-(4- [[[2-(2-methyl- 1 H-ihdol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide of compound formula- 1 obtained according to example-7.
  • Figure-8 Illustrates the PXRD pattern of novel crystalline Form-S of 2-(E)-N-hydroxy-3-(4- [[[2-(2-methyl- 1 H-indo!-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide of compound formula- 1 obtained according to example-8.
  • Figure-9 Illustrates the PXRD pattern of amorphous form of 2-(E)-N-hydroxy-3-[4- (((2-(2- methyl- 1 H-indol-3-yl)ethyl)amino]methyl]phenyl]-2-propenamide of compound formula- 1 obtained according to example-9.
  • Figure-10 Illustrates the PXRD pattern of crystalline Form-M of 2-(E)-N-hydroxy-3-[4-[((2- (2-methyl- 1 H-indol-3-yl)ethyl]amino]methy)]phenyl]-2-propenamide lactate compound of formula- l a.
  • Figure-11 Illustrates the PXRD pattern of crystalline Form-S of 2-(E)-N-hydroxy-3-[4-[[[2- (2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide lactate compound of formula- l a.
  • Figure-12 Illustrates the PXRD pattern of novel crystalline Form-N of 2-(E)-N-hydroxy-3- [4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]pheny l]-2-propenamide lactate.
  • Figure-13 Illustrates the PXRD pattern of crystalline Form-L of 2-(E)-N-hydroxy-3-[4- (([2- (2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide lactate compound of formula- l a.
  • Figure-14 Illustrates the PXRD pattern of crystalline Form-M I of (E)-methyl 3-(4-(((2-(2- methyl- 1 H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylate hydrobromide compound of formula-5a.
  • Figure-15 Illustrates the PXRD pattern of crystalline Form-M2 of (E)-methyl 3-(4-(((2-(2- methyl- 1 H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylate oxalate compound of formula-5b.
  • Figure-16 Illustrates the PXRD pattern of crystalline Form-M3 of 2-(E)-N-hydroxy-3-[4- [[[2-(2-methyl - 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide hydrobromide.
  • suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; "ether solvents” such as dimethoxy methane, tetrahydrofuran, 1 ,3-dioxane, 1 ,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1 ,2-dimethoxy ethane and the like; "ester solvents” such as methyl acetate,
  • suitable base used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as potassium hydride, lithium hydride and the like; “organic base” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, 1 ,8-diazabicyclo [5.4.0] undec-7-ene (DBU), !
  • inorganic bases like “alkali metal hydroxides”
  • DBN lithium dioisopropyl amide
  • LDA lithium dioisopropyl amide
  • n-butyl lithium tribenzylamine
  • isopropylamine diisopropylamine, diisopropylethyl amine, N- methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1 ,2,4-triazole, 1 ,4- diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
  • DABCO lithium dioisopropyl amide
  • the "suitable acid” used in the present invention can be selected from but not l imited to hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid, aceturic acid, phloretinic acid, phthalic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic
  • the first aspect of the present invention provides an amorphous form of 2-(E)-N- hydroxy-3-[4-[[[2-(2-methyl-1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide lactate compound of formula- 1 a.
  • the amorphous form of compound of formula- l a is characterized by its PXRD pattern as illustrated in figures 1 and 2.
  • the suitable solvent is selected from chloro solvents, ketone solvents, C i-C 6 alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ether solvents or their mixtures; and the dissolution of compound of formula- 1 in a suitable solvent or mixture of solvents can be carried out at 25-30° C or by heating the reaction mixture to a temperature ranging from 30°C to reflux temperature of the solvents employed;
  • suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, filtering, concentrating the reaction mixture, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures such as below 20° C to precipitate the solid followed by filtration or by any other suitable techniques.
  • a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures such as below 20° C to precipitate the solid followed by filtration
  • the solvent may be removed at temperatures ranging from 25°C to 100°C, optionally under reduced pressures.
  • the preferred embodiment of the present invention provides a process for the preparation of amorphous form of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl] amino]methyl]phenyl]-2-propenamide lactate compound of formula- l a, comprising of:
  • step-b) distilling off the solvent from the filtrate obtained in step-b) provides amorphous form of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyJ]amino]methyl]phenyl] -2- propenamide lactate compound of formula- 1 a.
  • step-b) spray drying the filtrate obtained in step-b) provides amorphous form of 2-(E)-N- hydroxy-3 -[4-(([2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propen amide lactate compound of formula- l a.
  • the second aspect of the present invention provides amorphous solid dispersion comprising of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl] phenyl]-2-propenamide lactate compound of formula- l a and at least one pharmaceutically acceptable excipient.
  • the excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cel lulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylceilulose acetate succinate (
  • the another embodiment of the present invention provides amorphous solid dispersion of 2-(E)-N-hydroxy-3-[4-[([2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propen amide lactate compound of formula- l a in combination with PVP-K-30 and the P-XRD pattern is depicted in figure-3.
  • amorphous solid dispersion comprising of 2-(E)-N-hydroxy-3-(4-([[2-(2-methyl- 1 H-indol-3- yl)ethyl]amino]methyl]phenyl]-2-propenamide lactate compound of formula- l a and at least one pharmaceutically acceptable excipient.
  • the said process comprising of:
  • step-a) the suitable excipient is same as defined above; the suitable solvent is same as defined in step-a) of the first aspect of the present invention; the suitable temperature ranges from 25°C to reflux temperature of the solvent used,
  • the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution;
  • step-b) the suitable techniques which may be used for the removal of solvent from the reaction mixture are same as defined in step-c) of the first aspect of the present invention
  • the solvent may be removed at temperatures ranging from 25°C to 1 00°C optionally under reduced pressures.
  • the ratio of the amount of weight of 2-(E)-N-hydroxy-3-(4- [[[2-(2-methyl-1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide lactate compound of formula- l a within the solid dispersion to the amount by weight of the excipient therein ranges from about 1 :0.05 to about 1 : 5.
  • the preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising of 2-(E)-N-hydroxy-3-(4-[[(2-(2- methyl-1 H-indol-3-yl)ethyl]amino]methyl]phenyl)-2-propenamide lactate compound of formula- l a and hydroxypropyl methylcellulose (HPMC).
  • the said process comprising of: a) Dissolving the 2-(E)-N-hydroxy-3-[4-[[(2-(2-methyl- 1 H-indol-3-yl)ethyl]amino] methyl]phenyl]-2-propenamide lactate compound of formula- l a and hydroxypropyl methylcellu!ose (HPMC) in methanol at 55-60°C,
  • amorphous solid dispersion comprising of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propen amide lactate compound of formula- l a with PVP-K-30, HPC and HPMC AS can be prepared.
  • the third aspect of the present invention provides novel crystalline forms of 2-(E)-N- hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide compound of formula- 1 , which includes:
  • step-a) filtering the precipitated solid to provide crystalline form-M of 2-(E)-N-hydroxy-3-[4- ([[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide compound of formula- 1 .
  • the suitable solvent is same as defined in step-a) of first aspect of the present invention; and the dissolution of compound of formula- 1 in a suitable solvent or mixture of solvents can be carried out at 25-30°C or by heating the reaction mixture to a temperature ranging from 30°C to reflux temperature of the solvents employed; in step-c) the suitable temperature is ranging from -20°C to 25°C.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline Form-M of 2-(E)-N-hydroxy-3-(4-(((2-(2-methvl- 1 H-indol-3-yl) ethyl]amino]methyl]phenyl]-2-propenamide compound of formula- 1 , comprising of:
  • the suitable solvent is selected from chloro solvents, ketone solvents, ether solvents, C
  • step-c) the suitable anti-solvent is ether solvents.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline Form-S of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl) ethyl]amino]methyl]phenyl]-2-propenamide compound of formula- ! , comprising of:
  • the fourth aspect of the present invention provides an amorphous form of 2-(E)-N- hydroxy-3-[4-([[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide of compound formula- 1 .
  • the amorphous form of compound of formula- 1 is further characterized by its PXRD pattern as illustrated in figure-9.
  • step-a) distilling off the solvent from the reaction mixture to provide amorphous form of 2- (E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2- propenamide compound of formula- 1 .
  • the suitable solvent is same defined in step-a) of the first aspect of the present invention.
  • the preferred embodiment of the present provides a process for the preparation of amorphous form of 2-(E)-N-hydroxy-3-(4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl] phenyl]-2-propen amide compound formula- 1 , comprising of:
  • the fifth aspect of the present invention provides a novel crystalline forms of 2-(E)-N- hydroxy-3-[4-(((2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide lactate compound of formula- l a, which includes:
  • In an embodiment of the present invention provides a process for the preparation of crystalline form-M of 2-(E)-N-hydroxy-3-[4-[([2-(2-methyl- 1 H-indol-3-yl)ethyl]amino] methyl]phenyl]-2-propenamide lactate compound formula- 1 a, comprising of: a) Adding a suitable solvent to 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl) ethyl]amino)methyl]phenyl]-2-propenamide lactate compound of formula- 1 a, b) stirring the reaction mixture,
  • the suitable solvent is selected from alcohol solvents
  • the temperature is ranging from 25°C to reflux temperature of the solvent
  • the suitable second solvent is selected from nitrile solvents
  • the preferred embodiment of the present provides a process for the preparation of crystalline form-M of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl)amino] methyl]phenyl]-2-propenamide lactate compound formula- 1 a, comprising of:
  • step-c) adding the reaction mixture obtained in step-c) to acetonitrile
  • the suitable solvent is selected from polar aprotic solvents, chloro solvents, ketone solvents, C
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl) ethyl]amino]methyl]phenyl]-2-propenamide lactate compound formula- l a, comprising of: a) Adding dimethyl formamide to 2-(E)-N-hydroxy-3-(4-[[[2-(2-methyl- 1 H-indol-3-yl) ethylJamino]methylJphenylJ-2-propenamide lactate compound of formula- 1 a, b) stirring the reaction mixture,
  • reaction mixture optionally filtering the reaction mixture, , .
  • step-a) the suitable solvent is same as defined in step-a) of the first aspect of the present invention; in step-c) the suitable temperature is ranging from -20°C to 10°C.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of 2-(E)-N-hydroxy-3-[4-[([2-(2-methyl- 1 H-indol-3-yl) ethyljamino] methyl]pheny!]-2-propenamide lactate compound formula- 1 a, comprising of: a) Adding 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyt] phenyl]-2-propenamide lactate compound of formula- l a to n-heptane,
  • the suitable solvent is selected from chloro solvents, ketone solvents, C 1 -C6 alcohol solvents, ester solvents, nitrile solvents, ether solvents or their mixtures; in step-b) the suitable temperature is ranging from 30°C to reflux temperature of the solvent used.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-L of 2-(E)-N-hydroxy-3-[4-[[(2-(2-methyl- 1 H-indol-3-yl) ethyl]amino)methyl]phenyl]-2-propenamide lactate compound formula- l a, comprising of: a) Adding isopropanol to 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl) amino]methyl]phenyl]-2-propenamide lactate compound of formula- l a,
  • the sixth aspect of the present invention provides an improved process for the preparation of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- ] H-indol-3-yl)ethyl]amino)methyl] phenyl]-2-propenamide lactate compound of formula- l a, comprising of:
  • step-b) treating the compound of formula-4 obtained in step-b) or compound of formula-5 obtained in step-c) with a suitable base in a suitable solvent followed by treating the obtained compound with aqueous hydroxylamine to provide 2-(E)-N-hydroxy-3 -[4- ([[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide compound of formula- 1 ,
  • step-(e) optionally purifying the compound obtained in step-(e) from a suitable solvent to provide pure compound of general formula- 1 ,
  • step-(a) treating the compound of general formula- 1 with a suitable base in a suitable solvent followed by treating the obtained compound with DL-lactic acid in a suitable solvent to provide 2-(E)-N-hydroxy-3-[4- [[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl] phenyl] -2 -propenamide lactate compound of formula- l a.
  • the suitable reducing agent is selected from Pd/C, NaB H4, Fe- acetic acid and Fe-hydrochloric acid;
  • the suitable base used is selected from organic or inorganic base
  • step-b) & e) the suitable acid is same as defined as above;
  • the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents like water or mixture thereof.
  • the preferred embodiment of the present invention provides an improved process for the preparation of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl] phenyl]-2-propenamide lactate compound of formula- 1 a, comprising of:
  • step-(b) purifying the compound obtained in step-(b) from methanol to provide pure compound of formula-5a
  • the seventh aspect of the present invention provides novel acid addition salts of (E)- methy] 3-(4-(((2-(2-methyl- 1 H-indol-3-y])ethyJ)amino)methyl)phenyl)acrylate compound of general formula-5.
  • the acid is selected from inorganic acids, such as hydro bromic acid, sul furic acid, nitric acid or phosphoric acid; and organic acids, such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, p-toluene sulfonic acid, ethane- 1 ,2- disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid.
  • organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic
  • the present invention provides (E)-methyl 3-(4-(((2-(2-methyl- 1 H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylate hydrobromide salt compound of formula- 5a and (E)-methyl 3-(4-(((2-(2-methyl- 1 H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylate oxalate salt compound of formula-5b.
  • step-a) the suitable reducing agent is same as defined in step-a) of the sixth aspect of the present invention; in step-b) the suitable acid is same as defined above; in step-a) and b) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents like water or mixture thereof.
  • the preferred embodiment of the present invention provides a process for the preparation of (E)-methyl 3-(4-(((2-(2-methyl- 1 H-indol-3-yl)ethyl)amino)methyl)phenyl) acrylate hydrobromide salt compound of formula-5a, comprising of:
  • the eighth aspect of the present invention provides crystalline form-M3 of 2-(E)-N- hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl)phenyl]-2-propenamide hydrobromide salt compound of formula- l b is further characterized by its PXRD pattern as illustrated in figure- 16.
  • the starting materials compound of formula-2 and compound of formula-3 can be prepared by using any of the prior known process.
  • the 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl] 2-propenamide lactate salt compound of formula- l a utilized as starting material for the preparation of novel crystalline forms of the present invention can be prepared by the process described in the present invention (or), any of the processes known in the art.
  • the intermediate compounds and their crystalline Form-M i and M2 of the present invention are useful for the preparation of pure compound of formula- l a.
  • solid state forms of compound of formula- l a of the present invention are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- l a is present in the composition in particular polymorphic form mentioned.
  • solid state forms of compound of formula- l a of the present invention can be micronized to achieve the desired better particle size distribution in order to make suitable formulation.
  • 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino]methyl]phenyl]-2- propenamide lactate compound of formula- l a obtained according to the present invention is having particle size distribution D90 ⁇ 200 ⁇ ; preferably ⁇ 1 00 ⁇ m.
  • 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3-yl)ethyl]amino)methyl)phenyl]-2- propenamide lactate compound of formula- l a produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. MiUing or micronization may be performed before drying, or after the completion of drying of the product.
  • compositions comprising compound of formula- 1 or salts thereof of the present invention.
  • pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument
  • the process of the present invention can be represented schematically as follows.
  • Example-1 Preparation of amorphous form of 2-(E)-N-hydroxy-3-[4- [ ⁇ [2-(2-methyl- 1 H- indol-3-yl)ethyl]amino]methyl]phenyl)-2-propenamide lactate: (Formula-l a)
  • Example-3 Preparation of amorphous solid dispersion of 2-(E)-N-hydroxy-3-
  • Example-4 Preparation of amorphous solid dispersion of 2-(E)-N-hydroxy-3-
  • Example-5 Preparation of amorphous solid dispersion of (2-(E)-N-hydroxy-3-
  • Example-6 Preparation of amorphous solid dispersion of 2-(E)-N-hydroxy-3-[4-[([2-(2- methyl-lH-indol-3-yl)ethyl]aminol methyl]phenyl)-2-propenamide lactate in combination with hydroxypropyl methyl cellulose-acetate succinate (HPMC-AS):
  • Example-7 Preparation of crystalline form-M of 2-(E)-N-hydroxy-3-(4-[((2-(2-methyl- 1 H- indol-3-yl)ethyl]amino]methyl] phenyl
  • Dimethylformamide (5 ml) was added to the compound of formula- 1 (0.5 gms) at 25- 30° C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 75- 80° C and stirred for 1 5 minutes at the same temperature. Cooled the reaction mixture to 25- 30° C. Filtered the solid and dried to get the title compound. Yield: 0.25 gms.
  • Example-8 Preparation of crystalline form-S of 2-(E)-N-hydroxy-3-
  • Example-9 Preparation of amorphous form of 2-(E)-N-hydroxy-3-(4-
  • Example-10 Preparation of crystalline form-N of 2-(E)-N-hydroxy-3-
  • n-Heptane ( 1 0 ml) was added to the compound of formula- l a (0.3 gms) at 25-30°C and stirred for 1 0 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the solid and dried to get the title compound. Yield : 0.2 gms.
  • Example-1 1 Preparation of 2-(2-methyl- 1 H- indol-3-yl)ethanamine: (Formula-2)
  • a mixture of phenyl hydrazine (1 00 gm), 5-chloropentan-2-one ( 1 1 7.07 gm) and water (500 ml) were stirred for 10 minutes at 25-30° C. Heated the reaction mixture to 65-75°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Toluene (500 ml) was added to the reaction mixture and stirred for 1 5 minutes. Separated both the organic and aqueous layers and washed the aqueous layers with toluene.
  • Toluene (800 ml) was added to the obtained aqueous layer followed by aqueous sodium hydroxide solution (44.3 gm of sodium hydroxide dissolved in 500 ml of water) to the reaction mixture and stirred for 1 5 minutes at 25-30°C. Heated the reaction mixture to 65-75°C and stirred for 1 5 minutes. Filtered the reaction mixture through hyflow bed at 65-70°C and washed the hyflow bed with toluene. Separated both the aqueous and organic layers and organic layers was charged into RBF and cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled toluene and drying to get the title compound. Yield: 105 gm.
  • Example-12 Preparation of (E)-methyl 3-(4-(((2-(2-methyl-1 H- indol-3-yl)ethyl)amino) methyl)phenyl)acrylate hydrobromide:
  • (Formula-5a) A mixture of 2-(2-methyl- 1 H-indol-3-yl)ethanamine (50 gm), (E)-methyl 3-(4- formylphenyl)acryiate (54.57 gm) and methanol (300 ml) were stirred for I 1 ⁇ 2 hour at 25-30° C. Cooled the reaction mixture to 0-5°C. Sodium borohydride (5.42 gm) was added lot wise to the reaction mixture for four times at the same temperature.
  • Example-13 Preparation of (E)-methyl 3-(4-(((2-(2-methyl-1 H- indol-3-yl)ethyl)amino) methyl)phenyl)acrylate hydrobromide: (Formula-5a)
  • Water (400 ml) was added to the reaction mixture at the same temperature. Acidified the reaction mixture with aqueous hydrobromic acid (600 ml) at 25-30°C and stirred for 2 hours. Filtered the solid and washed with water and suck dried the compound under reduced pressure to get the wet compound.
  • Methanol (600 ml) was added to the obtained wet compound at 25-30°C. Heated the reaction mixture to 60-70°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid and washed with methanol and drying to get the title compound.
  • Example-17 Preparation of 2-(E)-N-hydroxy-3-(4-
  • a solution of potassium hydroxide (2.9 gm of potassium hydroxide in 15 ml of methanol) was added to the reaction mixture and stirred for 10 minutes at 25-30°C.
  • Water 1 80 ml was added to the reaction mixture and stirred for 45 minutes at the same temperature. Filtered the compound and washed with water.
  • Water 132 ml was added to the reaction mixture and raised the temperature of the reaction mixture to 60-70°C.
  • the above prepared DL-Lactic acid solution was Slowly added to the reaction mixture. Cooled the reaction mixture to 30-35°C and stirred for 32 hours at the same temperature. Filtered the solid and washed with water and drying to get the title compound.
  • a mixture of DL-Lactic acid (30.27 gm) and water (216 ml) were stirred for 10 minutes at 25-30° C. Heated the reaction mixture to 90° C and stirred for 1 5 hours at the same temperature and kept a side.
  • a mixture of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl- 1 H-indol-3- yl)ethyl]amino]methyl]phenyl)-2-propenarnide hydrobromide (80 gms), tetrahydrofuran ( 1 .2 Itrs) and methanol ( 1 .2 Itrs) was stirred for 10 minutes at 25-30°C. Cooled the reaction mixture to 0-5°C.
  • the reaction mixture was basified using aqueous ammonia solution (40 ml) at 0-5°C and stirred for 60 minutes at the same temperature. Filtered the reaction mixture and washed with a mixture of THF and methanol. Water was added to the obtained wet compound at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the solid and washed with water. The above DL-Lactic acid solution was slowly added to a mixture of water and obtained wet compound within 45 minutes at 25-30°C. Filtered the reaction mixture and stirred the obtained filtrate for 35 hours at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound.
  • Example-19 Preparation of crystalline form-M of 2-(E)-N-hyd roxy-3-
  • Example-20 Preparation of crystalline form-S of 2-(E)-N-hydroxy-3-[4-
  • Example-19 Preparation of crystalline form-L of 2-(E)-N-hydroxy-3-

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Abstract

La présente invention concerne de nouvelles formes amorphes et cristallines de 2- (E)-N-hydroxy-3-[4- [[ [2- (2-méthyl -1 H-indol-3-yl)) éthyl] amino] méthyl] phényl]-2-propénamide et son sel de lactate ainsi que son procédé de préparation. (1a)
PCT/IN2017/000132 2016-11-21 2017-11-20 Procédé de préparation de l'acide 2- (e)-n-hydroxy-3-[4- [[ [2- (2-méthyl -1 h-indol-3-yl) éthyl] amino] méthyl] phényl]-2-propénamide 2-hydroxypropanoïque (1 : 1) et ses polymorphes WO2018092151A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007146716A2 (fr) * 2006-06-12 2007-12-21 Novartis Ag Polymorphes de n-hydroxy-3-[4-[[[2-(2-méthyl-1h-indol-3-yl)éthyl]amino]méthyl]phényl]-2e-2-propénamide
WO2007146717A2 (fr) * 2006-06-12 2007-12-21 Novartis Ag Procédé de fabrication des sels de n-hydroxy-3-[4-[[[2-(2-méthyl-1h-indol-3-yl)éthyl]amino]méthyl]phényl]-2e-2-propénamide
WO2008090534A1 (fr) * 2007-01-26 2008-07-31 Berand Limited Procédés et compositions destinés à l'inhibition d'un gain de poids excessif, la réduction de comportements alimentaires inappropriés et l'inhibition de l'hyperphagie pour le traitement de l'obésité

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007146716A2 (fr) * 2006-06-12 2007-12-21 Novartis Ag Polymorphes de n-hydroxy-3-[4-[[[2-(2-méthyl-1h-indol-3-yl)éthyl]amino]méthyl]phényl]-2e-2-propénamide
WO2007146717A2 (fr) * 2006-06-12 2007-12-21 Novartis Ag Procédé de fabrication des sels de n-hydroxy-3-[4-[[[2-(2-méthyl-1h-indol-3-yl)éthyl]amino]méthyl]phényl]-2e-2-propénamide
WO2008090534A1 (fr) * 2007-01-26 2008-07-31 Berand Limited Procédés et compositions destinés à l'inhibition d'un gain de poids excessif, la réduction de comportements alimentaires inappropriés et l'inhibition de l'hyperphagie pour le traitement de l'obésité

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SANJAY VERMA ET AL.: "A Systematic Approach to Design and Prepare Solid Dispersions of Poorly Water-Soluble Drug", AAPS PHARMSCITECH, vol. 15, no. 3, June 2014 (2014-06-01), pages 641 - 657, XP055485167 *

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