EP3286168A1 - Forme solide d'aprémilast et un procédé pour sa préparation - Google Patents

Forme solide d'aprémilast et un procédé pour sa préparation

Info

Publication number
EP3286168A1
EP3286168A1 EP16725347.5A EP16725347A EP3286168A1 EP 3286168 A1 EP3286168 A1 EP 3286168A1 EP 16725347 A EP16725347 A EP 16725347A EP 3286168 A1 EP3286168 A1 EP 3286168A1
Authority
EP
European Patent Office
Prior art keywords
apremilast
formula
tetrahydrofuran
solvate
thf
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.)
Withdrawn
Application number
EP16725347.5A
Other languages
German (de)
English (en)
Inventor
Iva OBADALOVA
Ondrej Dammer
Lukas KREJCIK
Jaroslava SVOBODOVA
Marcela Tkadlecova
Robert Klvana
Jan RYMES
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.)
Zentiva KS
Original Assignee
Zentiva KS
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.)
Filing date
Publication date
Priority claimed from CZ2015-277A external-priority patent/CZ2015277A3/cs
Priority claimed from CZ2016-226A external-priority patent/CZ2016226A3/cs
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP3286168A1 publication Critical patent/EP3286168A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to a novel solid form of apremilast of formula 2, ⁇ 3 ⁇ 4)-2-[l-(3-ethoxy-4- memoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-l,3-dione,
  • Apremilast is a novel inhibitor of phosphodiesterase PDE-4, i.e. a representative of a drug group that has tried to assert itself mainly in the treatment of the chronic obstructive pulmonary disease so far.
  • Apremilast causes inhibition of antiinflammatory cytokines and chemokines (TNF- ⁇ , IL-23, CXCL9 or CXCLIO).
  • cytokines and chemokines TNF- ⁇ , IL-23, CXCL9 or CXCLIO
  • apremilast directly modifies the formation thereof, and also interferes with the production of leukotriene PTB4, inducible NO synthase (iNOS) or metalloproteinases (MMP). It can be used for the treatment of psoriatic arthritis and is also being tested for the treatment of other inflammatory diseases. It represents a new small molecule for oral administration.
  • Forms A, B and F are described as pure polymorphic forms of apremilast, Forms C, D, E and G as solvates of apremilast (Form C - toluene, Form D - dichloromethane, Form E - acetonitrile, Form G - ethyl acetate).
  • Form C is presented as a toluene solvate that contains 3 molar equivalents of toluene per one mol of apremilast.
  • a reproduction of Form C provided a form that corresponds to the pattern of Form C of the patent application WO2009120167 with its X-ray powder pattern, but with the use of the thermal methods and !
  • Form D is presented as a dichloromethane solvate that contains 2.5 molar equivalents of dichloromethane per one mol of apremilast.
  • a reproduction of Form D provided a form that corresponds to the pattern of Form D of the patent application WO2009120167 with its X-ray powder pattern again, but with the use of the thermal methods and l H NMR measurement the content of dichloromethane was determined to be 1 molar equivalent. So according to our conclusions this is a dichloromethane solvate of apremilast in the molar ratio of 1 : 1.
  • Form E is presented as an acetonitrile solvate and Form G as an ethyl acetate solvate. Both these solvates are characterized in the patent application with the X-ray powder pattern and the records of the thermal methods.
  • This invention provides a THF solvate of apremilast (Form I-l), of formula 1, which is characterized especially by high stability and is easy to prepare.
  • Form I-l is excellent in high crystallinity, which makes it very suitable for the preparation of highly pure apremilast.
  • the invention further provides a process for preparing a solvate of (S)- ⁇ 2-[l-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylethyl] -4-acetylamraoisoindoline- 1 ,3-dione with tetrahydrofuran (1), comprising a reaction of either the amine (5)-3 with the anhydride 5, or a process comprising a reaction of a diastereoisomeric salt of the ( ⁇ S)-amine and tartaric acid, or their derivatives (S-6), wherein R 1 a R 2 are, independently from each other, H, a C1-Q2 alkyl, aryl or heteroaryl with one or more heteroatoms, wherein all these groups may be further substituted with any functional groups, with a base such as an alkaline hydroxide or alkaline carbonate, preferably sodium carbonate or potassium carbonate, producing the free amine (S)- 3, which subsequently reacts
  • any functional group refers to: (a) halogens, (b) hydroxy, alkoxy or aryloxy groups, (c) amino and nitro groups, (d) CHO and acyl groups (i.e. ketones), (e) derivatives of carboxylic acids.
  • the Y group in the derivatives 6 can in turn be a hydroxyl OH, O-substituted hydroxyl OR 4 , wherein R 4 is any C ⁇ - ⁇ alkyl, C 6 -C 14 aryl, heteroaryl with one or more heteroatoms, wherein all these groups may be further substituted with any functional groups.
  • the Y group in the derivatives 6 further also stands for NR 5 R 6 amides, wherein R s and R 6 are, independently from each other, H, a Ci-C 16 alkyl, a C6-C 14 aryl, heteroaryl with one or more heteroatoms, wherein all these groups can be further substituted with any functional groups, preferably C 6 -Ci 4 aryls substituted with halogens in any position (Scheme 3).
  • R l , R 2 H, C j -C j g alkyl, aryl, heteroaryl, " ⁇ ⁇ >
  • the obtained THF solvate (1) is easy to prepare, stable, exhibits high crystallmity and can be advantageously used for the preparation of pure apremilast with HPLC purity exceeding 99.9%. It can also easily be used for the preparation of amorphous apremilast (2).
  • This invention provides a THF solvate of apremilast (Form I-l) that is highly stable, exhibits high crystallinity and in addition it is easy to prepare.
  • Form I-l of apremilast exhibits a strongly crystalline character.
  • the X-ray powder pattern of this salt is shown in Fig. 1. Its characteristic diffractions with the use of CuKa radiation are 8.0; 12.7; 15.8; 19.4; 21.3 and 25.2 ⁇ 0.2 °2-theta.
  • Form I-l further exhibits the following characteristic reflections: 8.8; 9.1; 11.8; 15.3; 18.1 and 20.2+ 0.2 °2-theta; Diffraction peaks with a higher relative intensity than 15% are summarized in Table 1.
  • Table 1 Diffraction peaks of apremilast Form I-l
  • Form I-l of apremilast The melting point of the crystalline Form I-l of apremilast determined with the DSC analysis is 79.4°C (Fig. 3). According to the thermogravimetric analysis (TGA), Form I-l of apremilast contains 8.2 % of tetrahydrofuran (Fig. 4). It means that it is the hemisolvate of apremilast with tetrahydrofuran. Since tetrahydrofuran is a highly inert solvent, this Form 1-1 is also suitable for preparation of a dosage form.
  • TGA thermogravimetric analysis
  • Preparation of apremilast Form 1-1 comprises the following steps:
  • the dissolution or dispersion in tetrahydrofuran can be carried out at a temperature in the range from 20°C to the boiling point of the solvent. Subsequently, the mixture is usually cooled down to a temperature of 0°C to 30°C, preferably to the range of 20°C to 25°C and left to crystallize.
  • the salt can be isolated either directly by filtration, or concentration of the mixture, or evaporation of the solvents may follow.
  • Form 1-1 of apremilast can also be directly prepared during the formulation process, preferably directly during wet granulation. Apremilast together with the excipients is charged into a homogenizer and Form 1-1 is produced during wet granulation.
  • a solid state 13 C NMR measurement confirmed a hitherto undescribed, new Form 1-1 (Fig. 2).
  • Form 1-1 can be advantageously used to increase the chemical purity of apremilast. This form crystallizes well and removes impurities from apremilast. Conversion of Form B to Form 1-1 has increased the chemical purity from 99.12% (starting Form B) to 99.59% (final Form 1-1). Also, recrystallization of Form 1-1 itself increases the chemical purity from the initial 99.59% to the final 99.98% (HPLC).
  • the prepared Form 1-1 of apremilast according to this invention can be used for the preparation of pharmaceutical compositions, especially solid dosage forms, e.g. tablets.
  • Such pharmaceutical mixtures can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystaliine cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants, etc.
  • These tablets can be coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.
  • the invention further provides a process for preparing a solvate of (S)- ⁇ 2-[l-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylemyl]-4-acetylaniinoisoindoline-l J 3-dione with tetrahydrofuran (1), comprising either a reaction of the amine (S)-3 with the anhydride 5 in a mixture of tetrahydrofuran/a C2-C5 carboxylic acid, preferably in a mixture of telrahydrofuran/acetic acid, or a process comprising first a reaction of a diastereoisomeric salt of the amine and tartaric acid or their derivatives (S-6) with a base; preferentially using (R,R)- 4-chlorotartranilate (S-6a) or ( ⁇ -O ⁇ '-di- -toluoyl-tartrate (S-6b), producing the free amine (5)-3, which subsequently
  • the latter can be prepared by precipitation into an antisolvent, best water, or into an organic solvent selected from MTBE or heptane, by drying in the temperature range of 60-100°C, or by spray-drying from a solution with methanol, ethanol, dichloromethane or acetone.
  • An advantage of the process according to the invention is its easy performance, a high yield, low number of the operation steps and high purity of the crude product already.
  • room temperature refers, for the purposes of the text below and above, to the temperature range from 22 to 26°C.
  • Fig. 1 XRPD pattern of apremilast Form I-l
  • Fig. 2 ssNMR record of apremilast Form I-l
  • Apremilast was prepared according to the procedure published in the patent application WO2003080049.
  • the chemical purity of apremilast prepared this way was 99.4% (HPLC).
  • the 1H and 13 C NMR spectra confirmed the structure of apremilast.
  • the XRPD and DSC record confirmed Form B as described in the patent applications WO2003080049 and WO2009120167.
  • a 500ml three-neck flask was fitted with a mechanical stirrer, thermometer and cooler. 25 g (56 mmol) of the salt of (5)-2-(3-emoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine with N-acetyl-Z-leucine, 12.1 g (58.8 mmol) of 3-acetamidophtalic anhydride and 250 ml of glacial acetic acid were charged into a reaction vessel. The mixture was refluxed overnight and then cooled down to ⁇ 50°C.
  • the solvent 250 ml of acetic acid was removed in vacuo and the residue, having rich yellow colour, was dissolved in 800 ml of ethyl acetate. The obtained solution was washed with water (2 x 250), saturated aqueous NaHC0 3 (2 x 250 ml), brine (2 x 250 ml) and dried with sodium sulphate.
  • the solvent 800 ml of ethyl acetate was evaporated in vacuo and the residue was recrystallized from a binary solvent containing 150 ml of ethanol and 75 ml of acetone. The solid was isolated by filtration in vacuo and washed with 2 x 100 ml of ethanol. The product was dried in vacuo at 60°C until constant weight, which provided 19.1 g of the title compound; yield 74%, HPLC purity 99.29%, XRPD confirmed Form B.
  • the organic phase was separated and the aqueous phase was gradually extracted with 1 x 1500 ml of CH 2 C1 2 (30-33°C) and then with 1 x 900 ml of CH 2 C1 2 (30-33°C).
  • the combined dichloromethane phases were concentrated to the volume of ca. 1400-1600 ml and then 2400 ml of THF was added. Then, at the atmospheric pressure, ca. 2300 ml of the solvent was removed by distillation, the mixture was cooled down to 60°C and 500 ml of MTBE was added. After that, the mixture was gradually cooled down to -10°C during 1.5 h, seeded and stirred at -10°C for another 1.5 h.
  • the separated product was filtered off, washed with 2 x 120 ml of cooled THF and dried in a vacuum drier at 45-50°C. 254.5 g (83%) of white crystals of the title compound of formula (S)-3 was obtained.
  • the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad Soller slits and a 1 ⁇ 4° anti-diffusion slit were used.
  • For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.
  • the nuclear magnetic resonance (NMR) spectra were measured using a Bruker Avance 500 device.
  • the l H spectra were measured at the frequency of 500.13 MHz, 13 C at the frequency of 125.8 MHz.
  • the sample was measured in a deuterated solvent specified for the particular analysis, normally at 25°C (unless specified otherwise for a particular analysis).
  • the chemical shift ⁇ is expressed as ppm, the interaction constants J are specified in Hz.
  • the spectra were normally referenced to the residual solvent content.
  • Carbon spectra of solid-state nuclear magnetic resonance (ssNMR) were measured with the use of an Avance 400 WB Bruker device, using the CP/MAS method in a 4mm rotor at the speed of 13 kHz, normally at 25°C.
  • the records of the differential scanning calorimetry (DSC) were measured using a DSC Pyris 1 device made by the company Perkin Elmer.
  • the sample charge in a standard Al pot (40 ⁇ ,) was between 2-4 mg and the heating rate was 10°C/min.
  • the temperature program that was used consists of 1 min stabilization at the temperature of 20°C and then of heating up to 250°C at the heating rate of 10 °C/min.
  • As the carrier gas 4.0 N 2 was used at the flow of 20 ml/min.
  • the records of therniogravimetric analysis (TGA) were measured using a TGA 6 device made by the company Perkin Elmer,
  • the sample charge in a corundum pot was 20 mg and the heating rate was 10°C/min.
  • the temperature program that was used consists of 1 minute's stabilization at the temperature of 20°C and then of heating up to 300°C at the heating rate of 10°C/min.
  • As the carrier gas 4.0 N 2 was used at the

Abstract

L'invention concerne un solvate d'aprémilast avec du tétrahydrofuranne - THF de formule 1, le rapport molaire d'aprémilast à THF étant de 2 : 1. Le solvate de THF de l'aprémilast présente le point de fusion caractéristique de 79,4°C. Un aspect concerne un procédé de préparation du solvate de THF de l'aprémilast. Un autre procédé pour la préparation d'un solvate d'aprémilast avec du tétrahydrofuranne comprend une réaction de (S)-1-(3-éthoxy-4-méthoxyphényl)-2-(méthylsulfonyl)-éthylamine de formule (S)-3 avec de l'anhydride 3-acétamidophtalique de formule 5 dans un mélange de tétrahydrofuranne et d'un acide, ou une réaction d'un sel diastéréo-isomère de la (S)-1-(3-éthoxy-4-méthoxyphényl)-2-(méthylsulfonyl)-éthylamine avec de l'acide tartrique ou leurs dérivés de formule (S-6) avec une base, ce qui produit de la (S)-1-(3-éthoxy-4-méthoxyphényl)-2-(méthylsulfonyl)-éthylamine de formule (S)-3, et sa réaction avec de l'anhydride 3-acétamidophtalique de formule 5 dans un mélange de tétrahydrofuranne et d'un acide. Un autre aspect de la présente invention concerne une composition pharmaceutique comprenant le solvate de THF d'aprémilast et au moins un excipient pharmaceutiquement acceptable choisi dans le groupe formé par le lactose, la cellulose microcristalline, le croscarmellose de sodium et le stéarate de magnésium.
EP16725347.5A 2015-04-24 2016-04-20 Forme solide d'aprémilast et un procédé pour sa préparation Withdrawn EP3286168A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CZ2015-277A CZ2015277A3 (cs) 2015-04-24 2015-04-24 Pevná forma apremilastu a způsob její přípravy
CZ2016-226A CZ2016226A3 (cs) 2016-04-19 2016-04-19 Způsob přípravy THF solvátu apremilastu a amorfního apremilastu
PCT/CZ2016/000048 WO2016169533A1 (fr) 2015-04-24 2016-04-20 Forme solide d'aprémilast et un procédé pour sa préparation

Publications (1)

Publication Number Publication Date
EP3286168A1 true EP3286168A1 (fr) 2018-02-28

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ID=56083851

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EP16725347.5A Withdrawn EP3286168A1 (fr) 2015-04-24 2016-04-20 Forme solide d'aprémilast et un procédé pour sa préparation

Country Status (2)

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EP (1) EP3286168A1 (fr)
WO (1) WO2016169533A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN107686461A (zh) * 2016-08-04 2018-02-13 广东东阳光药业有限公司 阿普斯特的溶剂化物及其制备方法和用途
CN112305107A (zh) * 2020-10-23 2021-02-02 杭州朱养心药业有限公司 磷酸二酯酶-4抑制剂阿普斯特组合物及质量检测方法
CN114790164B (zh) 2021-08-13 2022-12-27 苏州璞正医药有限公司 一种取代的异吲哚啉-1,3-二酮类pde4抑制剂及其药物用途
CN113896674B (zh) * 2021-09-01 2023-10-27 深圳华中科技大学研究院 一种阿普斯特的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6020358A (en) 1998-10-30 2000-02-01 Celgene Corporation Substituted phenethylsulfones and method of reducing TNFα levels
US6962940B2 (en) 2002-03-20 2005-11-08 Celgene Corporation (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
KR20140142323A (ko) 2008-03-27 2014-12-11 셀진 코포레이션 (+)-2-[1-(3-에톡시-4-메톡시페닐)-2-메틸설포닐에틸]-4-아세틸아미노이소인돌린-1,3-디온을 포함하는 고체 형태, 이의 조성물, 및 이의 용도

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