WO2016112879A1 - Modification cristalline 2 de (3/?)-3-amino-l-[3-(trifluorométhyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-alpha]pyrazin-7-yl]-4-(2,4,5-trifluorophényl)butan-1-one l-tartrate - Google Patents

Modification cristalline 2 de (3/?)-3-amino-l-[3-(trifluorométhyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-alpha]pyrazin-7-yl]-4-(2,4,5-trifluorophényl)butan-1-one l-tartrate Download PDF

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Publication number
WO2016112879A1
WO2016112879A1 PCT/CZ2016/000001 CZ2016000001W WO2016112879A1 WO 2016112879 A1 WO2016112879 A1 WO 2016112879A1 CZ 2016000001 W CZ2016000001 W CZ 2016000001W WO 2016112879 A1 WO2016112879 A1 WO 2016112879A1
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WIPO (PCT)
Prior art keywords
amino
tartrate
dihydro
trifluorophenyl
butan
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PCT/CZ2016/000001
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English (en)
Inventor
Jindrich Richter
Kamal JARRACH
Violetta Kiss
Eszter TIEGER
Jaroslav Havlicek
Ondrej Dammer
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Zentiva, K.S.
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Publication of WO2016112879A1 publication Critical patent/WO2016112879A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to crystalline Modification 2 of (3R)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5H-[l i 2,4]triazolo[4,3-a]pyrazin-7-yll-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate of Formula 1,
  • Sitagliptin is a selective dipeptidyl-peptidase-4 (DPP-4) receptor inhibitor, used for the treatment of diabetes mellitus type 2 controlling the glucose (sugar) level of the blood.
  • DPP-4 is an enzyme that controls the incretin hormones. The level of the incretin hormones increases as an effect of saxagliptin and in parallel, pancreas produces more insulin and the amount of glucose produced by the liver decreases. These effects reduce the blood glucose level and help in the control of type-2 diabetes.
  • Sitagliptin is disclosed and a list of pharmaceutically acceptable salts thereof is generally included in patent WO03004498.
  • WO2004087650 discloses the sitagliptin free base in crystalline form.
  • WO2005003135 claims the dihydrogenphosphate salt of sitagliptin and its crystalline monohydrate. Three crystalline, anhydrous polymorphic forms of sitagliptin phosphate and various solvates are described and disclosed in patent WO2005020920. WO2005030127 claims a fourth anhydrous polymorph of sitagliptin phosphate. The amorphous dihydrogenphosphate is described and disclosed in patent WO2006033848. Further crystalline solid phase of sitagliptin dihydrogenphosphate are described and claimed patents US2009/247532 and WO2010131035. WO2012166420 claims the phosphate salt of sitagliptin in a stoichiometric ratio of 2:1.
  • Crystalline salts of sitagliptin and hydrochloric acid ben, D- and ..-tartaric acid, p- toluenesulfonic acid, benzenesulfonic acid and (lS)-(+)- and fl/?H-j-camphorsulfonic acid a[- e disclosed in patent WO2005072530.
  • WO 2009085990 claims crystalline salts of sitagliptin formed with sulfonic acid, hydrobromic acid, methanesulfonic acid, acetic acid, benzoic acid, oxalic acid, succinic acid, lactic acid and fumaric acid.
  • WO 2010000469 claims various polymorphic forms of salts of sitagliptin and hydrochloric acid, fumaric acid, sulfuric acid, succinic acid, glycolic acid, maleic acid, methanesulfonic acid, malic acid, phosphoric acid, lactic acid and citric acid. Salts of sitagliptin formed with ethanesulfonic acid, lactic acid, thiocyanic acid and glutaric acid are disclosed in patent WO2010012781.
  • WO2010092090 discloses sitagliptin salts of (D)- and (ij-glucuronic acid, glutaric acid, sulfuric acid, (D)- and (L)-lactic acids, ethanesulfonic acid, oxalic acid, acetic acid, (D)- and (L)- mandelic acid, capric acid, benzoic acid, hippuric acid, frans-cinnamic acid, malonic acid, citric acid, l-hydroxy-2-naphtolic acid, crotonic acid and ascorbic acid.
  • WO2011018494 claims various crystalline forms of sitagliptin salt formed with fumaric acid.
  • WO2012007455 describes the orotate salt of sitagliptin in amorphous phase.
  • the objective of the present invention to provide a novel crystalline modification of a L-tartrate Salt of sitagliptin with good chemical purity, chemical and physical stability and good processability during its preparation as an active pharmaceutical ingredient. It is very important from economical point of view that the preparation process is suitable for industrial scale application and easily reproducible.
  • the object of the present invention is to provide a novel crystalline modification of (3R)-3- amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 2, in particular in a solid form suitable for oral administration which has advantages over the prior art, for example with respect of stability, solubility of the pharmacologically active compound.
  • the invention further relates to pharmaceutical formulations containing the novel crystalline modification of (BRi-B-amino-l-tB-itrifluoromethy -e ⁇ -dihydro-SH-Il ⁇ iAltriazoloI iS- o]pyrazin-7-yl]-4- ⁇ 2,4,5-trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 2.
  • Figure 1 is an XRPD pattern of the crystalline Modification 2 of (3i?)-3-amino-l-[3- (trifluoromethy - ⁇ S-dihydro-SH-t ⁇ triazolo S-olpyrazin-y-yll- -t ⁇ B- trifluorophenyl)butan-l-one L-tartrate
  • Figure 2 is a FTIR spectra of the crystalline Modification 2 of ⁇ 3R)-3-amino-l-[3- (trifluoromethy -e ⁇ S-dihydro-SH-tl ⁇ ltriazolot ⁇ S-olpyrazin-T-yll- -t ⁇ ⁇ - trifluorophenyl)butan-l-one L-tartrate
  • Figure 3 is a Raman spectra of the crystalline Modification 2 of ⁇ 3R)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5H-[l i 2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate
  • Figure 4 is a ⁇ C-ssNMR spectra of the crystalline Modification 2 of ⁇ 3R)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5H-[l,2,4]triazolo[4 J 3- ]pyrazin-7-yl]-4- ⁇ 2 i 4,5- trifluorophenyl)butan-l-one L-tartrate
  • Figure 5 is a 19 F-ssNMR spectra of the crystalline Modification 2 of (3R)-3-amino-l-[3- (trifluoromethyl)-6 J 8-dihydro-5H-[l,2 ; 4]triazolo[4 ; 3-o]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate
  • Figure 6 is a DCS curve of the crystalline Modification 2 of (3/?)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5H-[l ; 2,4]triazolo[4 / 3-o]pyrazin-7-yl]-4-(2 i 4 / 5- trifluorophenyl)butan-l-one L-tartrate
  • Figure 7 is a TG curve of the crystalline Modification 2 of (3R)-3-amino-l-[3- ⁇ trifluoromethyl)- 6 i 8-dihydro-5H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one L- tartrate
  • the invention relates to a novel crystalline modification of (3R)-3-amino-l-[3- (trifluoromethyl)-6,8-dihydro-5H-[l,2 J 4]triazolo[4 ; 3-a]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one L-tartrate referred to herein as crystalline Modification 2, which meets the pharmaceutical requirements regarding the physico-chemical properties and stability and have advantages over the prior art, for example with respect of stability, solubility of the pharmacologically active compound, and which can be produced in reproducible manner even in industrial scale.
  • the novel crystalline Modification 2 of (3 ? ⁇ -3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H- [l,2,4]triazolo[4 i 3-a]pyrazin-7-yl]-4- ⁇ 2,4 i 5-trifluorophenyl)butan-l-one L-tartrate according to the invention has the characteristic XRPD pattern as shown in Figure 1. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • Modification 2 can be further characterized by an FTIR, Raman and solid state NMR spectroscopy investigations.
  • Figure 2 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 3446, 3364, 3035, 1668, 1627, 1276, 1148, 1023, 877 and 716 cm "1 and
  • Figure 3 shows the Raman (FT-Raman Bruker RFS 100/S) spectrum comprising characteristic peaks at 3091, 3036, 2970, 2913, 1631, 1512, 1370, 801, 757 and 232 cm "1 .
  • Figure 4 shows the 13 C-ssNMR (Bruker AVANCE 250 MHz) spectrum
  • Figure 5 shows the 19 F-ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • (2,4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 2 can be prepared by a salt formation and crystallization process comprising the steps of
  • step 1) any crystalline solid form of (3/?)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H- [l,2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one L-tartrate can be used as starting material.
  • L-tartrate can be suspended in alcohol- water mixtures, preferably in a methanol-water solvent mixture in a volumetric ratio of 90:10 to 50:50, preferably 60:40.
  • the temperature applied for suspension depends on the initial amount and solid form of the starting material, preferably 20°C -30°C, more preferably 25°C.
  • step 2) the suspension containing (3/?)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5H- [l,2,4]triazolo[4,3-o]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-l-one L-tartrate can be agitated for further 1 to 3 weeks, preferably 2 weeks.
  • step 3) the crystals obtained can be collected by any conventional method, e.g. filtration.
  • the obtained (SRj-B-amino-l-tS-ttrifluoromethy -e ⁇ -dihydro-BH-Il ⁇ triazolo ⁇ S- a]pyrazin-7-yl]-4- ⁇ 2,4,5-trifluorophenyl)butan-l-one L-tartrate crystalline Modification 2 can be dried by vacuum suction or at laboratory condition, preferably by vacuum suction.
  • the slurry was agitated at room temperature for 2 weeks and then the resulted solid was collected by filtration and dried on air by vacuum suction.
  • the slurry was heated up to 50°C with a continuous stirring of 200 rpm.
  • the suspension was stirred for additional 1 hour at 50°C and cooled back to 20°C with a cooling rate of 15°C/h and stirred for 2 hours at that temperature.
  • the product was filtered and dried in vacuum oven at 40°C and 200 mbar for 16 hours.
  • the resulting suspension was stirred for additional 15 minutes at 50°C and cooled to 20°C with a cooling rate of 15°C/h and stirred for 1 hour at that temperature.
  • the product was filtered and dried in vacuum oven at 40°C and 200 mbar for 16 hours.
  • Hi-N R analysis confirmed the structure with a stoichiometry of 1:1.
  • Water content determination resulted in 1.5% of water content.
  • Incident beam optics programmable divergence slits (irradiated length 10 mm), 10 mm mask, 1/ 9 anti-scatter fixed slit, 0.02 rad Soller slits.
  • Diffracted beam optics X'Celerator detector, scanning mode, active length 2.122 Q , 0.02 rad Soller slits, anti-scatter slit 5.0 mm, Ni filter.
  • FTIR spectra were recorded by Nicolet Thermo 6700 spectrometer.
  • ⁇ NMR spectra the Bruker NMR spectrometer AVANCE 500 MHz and DMSO as solvent were used. The stoichiometry of salts were determined from integrals of corresponding signals of API and counterion. C and F ss N R spectra were measured on Bruker 400 WB spectrometer in 4 mm rotors with 13 kHz spinning frequency. The spectra of salts were compared with the spectrum of initial API because the formation of a salt should be accompanied by changes of positions of signals of API and by the presence of signals of counterion.
  • the samples were weighed in aluminium pans and covers (20 ⁇ .) and measured in a nitrogen flow (50 mL/min). Investigations were performed in a temperature range of 25 °C to 300 °C with a heating rate of 10°C/min.
  • the temperatures specified in relation to DSC analyses are the temperatures of the peak maxima and onset temperature of peaks.
  • the specific heat is given in J/g.
  • the weight of the sample was about 3-4 mg.
  • the samples were weighed in aluminium pans (85 ⁇ .) and measured in nitrogen flow. TGA investigations were performed in a temperature range of 25°C to 300°C with a heating rate of 10°C/min.
  • the weight of the sample was about 5-6 mg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Modification cristalline 2 du sel de l'acide L-tartrique de sitagliptine présentant les pics de diffraction caractéristiques suivants : 5,83; 15,63; 17,73; 25,58; 26,44 ± 0,2° 2-thêta. (Formule)
PCT/CZ2016/000001 2015-01-13 2016-01-07 Modification cristalline 2 de (3/?)-3-amino-l-[3-(trifluorométhyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-alpha]pyrazin-7-yl]-4-(2,4,5-trifluorophényl)butan-1-one l-tartrate WO2016112879A1 (fr)

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CZ2015-30580U 2015-01-13
CZ2015-30580U CZ27898U1 (cs) 2015-01-13 2015-01-13 Krystalická modifikace 2 L-vínanu (3R)-3-amino-1-[3-(trifluormethyl)-6,8-dihydro-5H-[1,2,4,]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorfenyl)butan-1-onu

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Citations (18)

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WO2003004498A1 (fr) 2001-07-06 2003-01-16 Merck & Co., Inc. Pyrazines beta-amino tetrahydroimidazo (1, 2-a) et pyrazines tetrahydrotrioazolo (4, 3-a) utilisees en tant qu'inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
WO2004087650A2 (fr) 2003-03-27 2004-10-14 Merck & Co. Inc. Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv
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WO2009085990A2 (fr) 2007-12-20 2009-07-09 Dr. Reddy's Laboratories Limited Procédés de préparation de sitagliptine et sels pharmaceutiquement acceptables de celle-ci
US20090247532A1 (en) 2008-03-28 2009-10-01 Mae De Ltd. Crystalline polymorph of sitagliptin phosphate and its preparation
WO2010000469A2 (fr) 2008-07-03 2010-01-07 Ratiopharm Gmbh Sels cristallins de sitagliptine
WO2010012781A2 (fr) 2008-07-29 2010-02-04 Medichem, S.A. Nouvelles formes cristallines de sels d’un dérivé de 5,6,7,8-tétrahydro-1,2,4- triazolo[4,3-a]pyrazine
WO2010032264A2 (fr) * 2008-08-27 2010-03-25 Cadila Healthcare Limited Procédé amélioré de préparation de (2r)-4-oxo-4-[3-(trifluorométhyl)-5,6-dihydro[1,2,4]-triazolo [4,3-a]pyrazin-7(8h)-yl]-1-(2,4,4-trifluorophényl)butan-2-amine et nouvelles impuretés présentes lors de sa préparation
WO2010092090A2 (fr) 2009-02-11 2010-08-19 Lek Pharmaceuticals D.D. Nouveaux sels de la sitagliptine
WO2010131035A1 (fr) 2009-05-11 2010-11-18 Generics [Uk] Limited Nouveau polymorphe cristallin du dihydrogénophosphate de sitagliptine
WO2011018494A1 (fr) 2009-08-13 2011-02-17 Sandoz Ag Composé cristallin de 7- [ (3r) -3-amino-1-oxo-4- (2, 4, 5-trifluorophényl) butyl] -5, 6, 7, 8-tétrahydro-3- (trifluorométhyl) -1, 2, 4 -triazolo [4,3-a] pyrazine
WO2012007455A1 (fr) 2010-07-13 2012-01-19 Chemo Iberica, S.A. Procédé de préparation de sels organiques
WO2012166420A1 (fr) 2011-05-27 2012-12-06 Merck Sharp & Dohme Corp. Sels d'acide phosphorique de la sitagliptine
WO2015062562A1 (fr) * 2013-11-01 2015-05-07 Zentiva, K.S. Polymorphe stable du sel de (2r)-4-oxo-4-[3-(trifiuorométhyl)-5,6- dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-1-(2,4,5-trifluorophényl)butan-2-amine avec du l-acide tartrique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003004498A1 (fr) 2001-07-06 2003-01-16 Merck & Co., Inc. Pyrazines beta-amino tetrahydroimidazo (1, 2-a) et pyrazines tetrahydrotrioazolo (4, 3-a) utilisees en tant qu'inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
WO2004087650A2 (fr) 2003-03-27 2004-10-14 Merck & Co. Inc. Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv
WO2005003135A1 (fr) 2003-06-24 2005-01-13 Merck & Co., Inc. Sel d'acide phosphorique d'un inhibiteur de la dipeptidyl peptidase iv
WO2005020920A2 (fr) 2003-09-02 2005-03-10 Merck & Co., Inc. Nouvelles formes cristallines d'un sel d'acide phosphorique d'un inhibiteur de dipeptidyl peptidase-iv
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WO2005072530A1 (fr) 2004-01-16 2005-08-11 Merck & Co., Inc. Nouveau sel cristallin d'un inhibiteur de dipeptidyle peptidase-iv
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WO2009085990A2 (fr) 2007-12-20 2009-07-09 Dr. Reddy's Laboratories Limited Procédés de préparation de sitagliptine et sels pharmaceutiquement acceptables de celle-ci
US20090247532A1 (en) 2008-03-28 2009-10-01 Mae De Ltd. Crystalline polymorph of sitagliptin phosphate and its preparation
WO2010000469A2 (fr) 2008-07-03 2010-01-07 Ratiopharm Gmbh Sels cristallins de sitagliptine
WO2010012781A2 (fr) 2008-07-29 2010-02-04 Medichem, S.A. Nouvelles formes cristallines de sels d’un dérivé de 5,6,7,8-tétrahydro-1,2,4- triazolo[4,3-a]pyrazine
WO2010032264A2 (fr) * 2008-08-27 2010-03-25 Cadila Healthcare Limited Procédé amélioré de préparation de (2r)-4-oxo-4-[3-(trifluorométhyl)-5,6-dihydro[1,2,4]-triazolo [4,3-a]pyrazin-7(8h)-yl]-1-(2,4,4-trifluorophényl)butan-2-amine et nouvelles impuretés présentes lors de sa préparation
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WO2010131035A1 (fr) 2009-05-11 2010-11-18 Generics [Uk] Limited Nouveau polymorphe cristallin du dihydrogénophosphate de sitagliptine
WO2011018494A1 (fr) 2009-08-13 2011-02-17 Sandoz Ag Composé cristallin de 7- [ (3r) -3-amino-1-oxo-4- (2, 4, 5-trifluorophényl) butyl] -5, 6, 7, 8-tétrahydro-3- (trifluorométhyl) -1, 2, 4 -triazolo [4,3-a] pyrazine
WO2012007455A1 (fr) 2010-07-13 2012-01-19 Chemo Iberica, S.A. Procédé de préparation de sels organiques
WO2012166420A1 (fr) 2011-05-27 2012-12-06 Merck Sharp & Dohme Corp. Sels d'acide phosphorique de la sitagliptine
WO2015062562A1 (fr) * 2013-11-01 2015-05-07 Zentiva, K.S. Polymorphe stable du sel de (2r)-4-oxo-4-[3-(trifiuorométhyl)-5,6- dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-1-(2,4,5-trifluorophényl)butan-2-amine avec du l-acide tartrique

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