Classifications

• • 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 a novel salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl ⁇ pyrazol-l-yl]propanenitrile of Formula I
• the present invention relates to a pharmaceutically acceptable salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and one acid component selected from the group consisting of benzoic acid, benzenesulphonic acid, 4-chlorobenzenesulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, 2-naphthalenesulphonic acid, L-tartaric acid and p-toluenesulphonic acid.
• the invention also relates to processes of preparation of salts as well as to their use in pharmaceutical compositions.
• Use of solid forms of ruxolitinib and manufactured salts in the preparation of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile in the free form or in the form of any pharmaceutical salt thereof is also part of the invention.
• WO2007070514 describes protein kinase inhibitors with valuable pharmacological effect in the treatment of related diseases.
• One example of the compounds disclosed is (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile. Preparation of the base is also described.
• the object of the present invention is to provide novel pharmaceutically acceptable salts of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4"yl)pyrazol-l-yl]propanenitrile and one acid component selected form the group consisting of benzoic acid, benzenesulphonic acid, 4-chlorobenzenesulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, 2-naphthalenesulphonic acid, L-tartaric acid and p-toluenesulphonic acid in amorphous form and methods of their production.
• These salts can be used to prepare ruxolitinib salts and to prepare formulation thereof.
• novel salts of ruxolitinib are as follows:
• ruxolitinib and ruxolitinib salts consists in their good physical and chemical characteristics, which make them suitable for preparation of a dosage form.
• these salts are easily producible by a 1-step method in polar aprotic solvents, preferebly in acetonitrile, methanol and ethanol with an excellent chemical purity.
• polymorph The ability of a compound to crystallize in different crystalline phases is called polymorphism.
• polymorph may include the amorphous phase (disordered), hydrates (water present in the crystal lattice) and solvates (solvents other than water present in the crystal lattice).
• the difference in the crystal lattice of the crystalline modifications of a compound is expressed in different crystal symmetry and unit cell parameters which appears as the X-Ray diffraction characteristics of a crystalline powder.
• the different crystalline modifications generate different set of angles and different values of the intensity and fmnaly result in different X-Ray powder diffractogram.
• Amorphous phases lack the long-range order characteristic of a crystal. The absence of crystallinity is easily observed in an X-Ray powder diffractogram. Therefore, the X-Ray Powder Diffractogram can be used to identify different crystalline modifications as well as the amorphous phase.
• the term ruxolitinib salts referes to ruxolitinib salts, as used in this patent application, is synonymous to commonly used expressions tiltamorphous ruxolitinib salts".
• the term fluffyroom temperature is defined as a temperature between 15°C and 30°C; preferably it is between 20-25°C or about 25°C.
• the present invention further relates to pharmaceutical formulations comprising one of the novel salts of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and to the use thereof for the treatment of myelofibrosis.
• Figure 1 is an FTIR spectra of the salt of (3R)-3-cyclopentYl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and benzoic acid prepared according to Example 1;
• Figure 2 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4- ⁇ 7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and benzoic acid prepared according to Example l;
• Figure 3 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and benzoic acid prepared according to Example
• Figure 4 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4- ⁇ 7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and benzoic acid prepared according to Example 1;
• Figure 5 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and benzoic acid prepared according to Example 1;
• Figure 6 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and benzenesulphonic acid prepared according to Example 2;
• Figure 7 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4- ⁇ 7H-pynOlo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and benzenesulphonic acid prepared according to Example 2;
• Figure 8 is a solid state N R pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pYrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and benzenesulphonic acid prepared according to Example 2;
• Figure 9 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[23-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and benzenesulphonic acid prepared according to Example 2;
• Figure 10 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and benzenesulphonic acid prepared according to Example 2;
• Figure 11 is an FT1R spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic acid prepared according to Example 3;
• Figure 12 is a 1H-N R spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic acid prepared according to Example 3;
• Figure 13 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimid'in-4-yl)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic acid prepared according to Example 3;
• Figure 14 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic acid prepared according to Example 3;
• Figure 15 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- y!)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic prepared according to Example 3;
• Figure 16 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and citric acid prepared according to Example 4;
• Figure 17 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yi]propanenitrile and citric acid prepared according to Example 4;
• Figure 18 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyI-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and citric acid prepared according to Example 4;
• Figure 19 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and citric acid prepared according to Example 4;
• Figure 20 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-t4-(7H-pyrrolo[2,3-d]pyrimidin-4- y!)pyrazol-l-yl]propanenttrile and citric acid prepared according to Example 4;
• Figure 21 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrro!o[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and ethanesulphonic acid prepared according to Example 5;
• Figure 22 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and ethanesulphonic acid prepared according to Example 5;
• Figure 23 is a solid state NMR pattern of the salt of ⁇ 3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and ethanesulphonic acid prepared according to Example 5;
• Figure 24 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrro!o[2,3- dIpyrimidin-4-yl)pyrazol-l-yl]propanenitrile and ethanesulphonic acid prepared according to Example 5;
• Figure 25 is a DSC curve of the salt of (3R)-3-cydopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidirt-4- yl)pyrazol-l-yl]propanenitrile and ethanesulphonic prepared according to Example 5;
• Figure 26 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4- ⁇ 7H-pyrroloi2 / 3-d]pyrimidin- 4-y!)pyrazo!-l-yl]propanenitri!e and fumaric acid prepared according to Example 6;
• Figure 27 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and fumaric acid prepared according to Example 6;
• Figure 28 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and fumaric acid prepared according to Example 6;
• Figure 29 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and fumaric acid prepared according to Example 6;
• Figure 30 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and fumaric prepared according to Example 6;
• Figure 31 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and hydrobromic acid prepared according to Example 7;
• Figure 32 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and hydrobromic acid prepared according to Example 7;
• Figure 33 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and hydrobromic acid prepared according to Example 7;
• Figure 34 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[23-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and hydrobromic acid prepared according to Example 7;
• Figure 35 is an FTIR spectra of the salt of ⁇ 3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[23-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and hydrochloric acid prepared according to Example 8;
• Figure 36 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitnle and hydrochloric acid prepared according to Example 8;
• Figure 37 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4- ⁇ 7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazoH-yl]propanenitrile and hydrochloric acid prepared according to Example 8;
• Figure 38 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- Yl)pyrazol-l-yl]propanenitrile and hydrochloric acid prepared according to Example 8;
• Figure 39 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[23-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and 2-naphthalenesulphonic acid prepared according to Example 9;
• Figure 40 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-Yl)pyrazol-l-yl]propanenitrile and 2-naphthalenesulphonic acid prepared according to Example 9;
• Figure 41 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pynrnidin-4-yl)pyrazol-l-yl]propanenitrile and 2-naphthalenesulphonic acid prepared according to Example 9;
• Figure 42 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidm-4-yl)pyrazol-l-Yl]propanenitrile and 2-naphthalenesulphonic acid prepared according to Example 9;
• Figure 43 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and 2-naphthalenesulphonic acid prepared according to Example 9;
• Figure 44 is an FTIR spectra of the salt of (3R)-3-CYclopentyl-3-[4-(7H-pYrrolo[2,3-d]pYrimidin- 4-yl)pyrazol-l-yl]propanenitrile and L-tartaric acid prepared according to Example 10;
• Figure 45 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-t4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and L-tartaric acid prepared according to Example 10;
• Figure 46 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and L-tartaric acid prepared according to Example 10;
• Figure 47 is an XRPD pattern of the salt of ⁇ 3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and L-tartaric acid prepared according to Example 10;
• Figure 48 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and L-tartaric acid prepared according to Example 10;
• Figure 49 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and p-totuenesulphonic acid prepared according to Example 11;
• Figure 50 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and p-toluenesulphonic acid prepared according to Example 11;
• Figure 51 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and p-toluenesulphonic acid prepared according to Example 11;
• Figure 52 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and p-toluenesulphonic acid prepared according to Example 11;
• Figure 53 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitriie and p-toluenesulphonic acid prepared according to Example 11.
• the aim of the present invention is to provide novel pharmaceutically acceptable salts of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile
• inventive salts may exist in different solid forms with different internal structures (polymorphism), which may have different physico-chemical properties. Therefore, pure crystalline forms and pure amorphous phase can be prepared, as well as mixtures of different crystalline forms in any ratio or mixtures of crystalline form ⁇ s) with the amorphous form.
• inventive salt formed from (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and at least one pharmaceutically acceptable acid component can be present in a crystalline form or in an amorphous form.
• the salts may be in an anhydrous and/or a solvent-free form; or they may be in a hydrated or sol ated form.
• All said salts can be prepared by the reaction of ⁇ 3R)-3-cyclopentyl-3-[4- ⁇ 7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazo!-l-yl]propanenitrile with an acid selected from the group consisting of benzoic acid, benzenesu!phonic acid, 4-chlorobenzenesulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, 2 ⁇ naphthalenesulphonic acid, L-tartaric acid and p-toluenesulphonic acid in a solvent selected from the group consisting of C1-C4 alkyl alcohols, acetates, ketones, nitriles and water and any of their mixtures, preferebly in methanol, ethanol, 2-propanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran and
• a salt of (3R)-3-cyclopentyl-3-[4- ⁇ 7H-pyrrolot2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and an acid component selected from the group consisting of benzoic acid, benzenesulphonic acid, 4-chlorobenzenesulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, 2-naphthalenesulphonic acid, L-tartaric acid and p- toluenesulphonic acid can be obtained by a process comprising the following steps: a) dissolving (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazoM- yl]propanenitrile in C1-C4 alkyl alcohols, acetates, ketones, nitriles and water or any of their mixtures, preferably in
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yi]propanenitrile and benzoic acid can be characterized by FTIR and IH-NMR spectroscopy investigations.
• Figure 1 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3197, 3130, 2941, 2863, 2254, 1584, 867, 831, 707 and 604 cm "1 wavenumbers.
• Figure 2 shows the IH-NMR (Bruker AVANCE 500) spectrum.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzoic acid has the characteristic XRPD pattern as shown in Figure 4.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzoic acid is an essentially amorhpous phase.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzenesulphonic acid can be characterized by FTIR and IH-NMR spectroscopy investgations.
• Figure 6 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3109, 2950, 2868, 2814, 2250, 1621, 1596, 1033, 729 and 610 cm "1 wavenumbers.
• Figure 7 shows the IH-NMR (Bruker AVANCE 500) spectrum.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzenesulphonic acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 8.
• the salt of (3R)-3-cyc!opentyl-3-[4-(7H-pyrrolo[2 / 3-d]pyrimidin-4-yl)pyrazol-l- yljpropanenitrile and benzenesulphonic acid has the characteristic XRPD pattern as shown in Figure 9.
• the salt of (S l-S-cycio entyl-S- ⁇ -tyH-pyrrolotZ ⁇ -dlpyrimidin ⁇ -yOpyrazol-l- y!]propanenitrile and benzenesulphonic acid is an essentially amorhpous phase.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzenesulphonic acid can be further described by thermal analytical method.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitriie and 4-chlorobenzenesulphonic acid has the characteristic XRPD pattern as shown in Figure 14.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic acid is an essentially amorhpous phase.
• T 0 nset 152.8.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-Yl)pyrazol-l- yl]propanenitrile and citric acid can be characterized by FTIR and IH-NMR spectroscopy investgations.
• Figure 16 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3116, 2950, 2869, 2251, 1716, 1584, 1343, 815, 738 and 615 cm 1 waven umbers.
• Figure 17 shows the IH-NMR (Bruker AVANCE 500) spectrum.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile and citric acid has the characteristic XRPD pattern as shown in Figure 19.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2 i 3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and citric acid is an essentially amorhpous phase.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and ethanesulphonic acid can be characterized by FTIR and IH-NMR spectroscopy investgations.
• Figure 21 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3108, 2947, 2869, 2812, 2249, 1620, 1596, 1153, 1034 and 740 cm "1 wavenumbers.
• Figure 22 shows the IH-NMR (Bruker AVANCE 500) spectrum.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and ethanesulphonic acid has the characteristic XRPD pattern as shown in Figure 24.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and ethanesulphonic acid is an essentially amorhpous phase.
• the salt of (3R)-3-cyctopentyl-3-[4-(7H-pyrrolo[2 ) 3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and fumaric acid can be characterized by FTIR and IH-NMR spectroscopy tnvestgations.
• Figure 26 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3118, 2951, 2868, 2251, 1699, 1582, 1558, 1344, 1258 and 734 cm 1 wavenumbers.
• Figure 27 shows the IH-NMR (Bruker AVANCE 500) spectrum.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazoi-l- yl]propanenitrile and fumaric acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 28.
• the salt of (3R)-3-cyclopenty!-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and fumaric acid has the characteristic XRPD pattern as shown in Figure 29.
• the salt of (3R)-3-cyclopentyl-3-(4-(7H-pyrrolot2,3-d]pyrimidin-4-yl)pyrazof-l- yl]propanenitrile and hydrobromic acid can be characterized by FTIR spectroscopy investgation.
• Figure 31 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3065, 2944, 2866, 2797, 2250, 1613, 1584, 1338, 815 and 741 cm 1 wavenumbers.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile and hydrobromic acid has the characteristic XRPD pattern as shown in Figure 33.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrtmidin-4-yl)pyrazol-l- yl]propanenitrile and hydrobromic acid is an essentially amorhpous phase.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and hydrochloric acid has the characteristic XRPD pattern as shown in Figure 37.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and hydrochloric acid is an essentially amorhpous phase.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and 2-naphthalenesulphonic acid can be characterized by FTIR and 1H-N R spectroscopy investgations.
• Figure 39 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3113, 2951, 2868, 2250, 1621, 1594, 1164, 1027, 816 and 673 cm 1 wavenumbers.
• Figure 40 shows the 1H-N R (Bruker AVANCE 500) spectrum.
• the salt of ⁇ 3R)-3-cyclopentyl-3-[4- ⁇ 7H-pyrro!o[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and 2-naphthalenesulphonic acid has the characteristic XRPD pattern as shown in Figure 42.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimid " in-4- yl)pyrazol-l-yl]propanenitrile and 2-naphthalenesulphonic acid is an essentially amorhpous phase.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile and L-tartaric acid can be characterized by FTIR and 1H-NMR spectroscopy investgations.
• Figure 44 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3118, 2947, 2866, 2250, 1718, 1583, 1122, 1075, 816 and 737 cm "1 wavenumbers.
• Figure 45 shows the 1H-NMR (Bruker AVANCE 500) spectrum.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile and L-tartaric acid has the characteristic XRPD pattern as shown in Figure 47.
• the salt of (3R)-3-CYClopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propaneriitrile and L-tartaric acid is an essentially amorhpous phase.
• )pyrazol-l- yl]propanenitrile and p-toluenesulphonic acid can be characterized by FTIR and IH-NMR spectroscopy investgations.
• Figure 49 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3109, 2950, 2867, 2250, 1620, 1596, 1162, 1008, 680 and 564 cm '1 wavenumbers.
• Figure 50 shows the IH-N (Bruker AVANCE 500) spectrum.
• the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and p-toluenesulphonic acid has the characteristic XRPD pattern as shown in Figure 52.
• -l- yl]propanenitrile and p-toluenesulphonic acid is an essentially amorhpous phase.
• Scan description scan type - gonio - measurement range 2 - 40 ⁇ 2 ⁇ step size 0.022 2 ⁇ step time: 300 s.
• Incident beam optics programmable divergence slits (irradiated length 10 mm). 10 mm mask. 1/49 anti-scatter fixed slit, 0.02 rad Soller slits.
• Diffracted beam optics X'Celerator detector, scanning mode, active length 2.122 ⁇ , 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.
• the temperatures specified in relation to DSC analyses are the temperatures of the peak maxima (T peak ) and onset temperature (T 0 nset) of peaks for the crystalline form and a glass transition temperature (Tg) of the amorphous form.
• the enthalpy is given in J/g.
• the weight of the sample was about 1.5-4.5 mg.
• the suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suctio .
• the sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.
• the suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction.
• HPLC purity 99.1% The sligthly yellowish powder obtained was analyzed by FT1R spectroscopy.
• the sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.
• the sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.
• the suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction.
• the sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.
• the sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.
• the suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction.
• the sligthly yellowish powder obtained was analyzed by FT1R spectroscopy. Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 7.
• the suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction.
• the sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.
• the sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (1)

Family

ID=54608211

Family Applications (1)

Country Status (4)

Cited By (5)

Families Citing this family (1)

Citations (5)

• 2014
  • 2014-11-10 CZ CZ2014-773A patent/CZ2014773A3/cs unknown
• 2015
  • 2015-11-05 EA EA201790985A patent/EA201790985A1/ru unknown
  • 2015-11-05 EP EP15797582.2A patent/EP3218379A1/en not_active Withdrawn
  • 2015-11-05 WO PCT/CZ2015/000133 patent/WO2016074650A1/en active Application Filing

Patent Citations (6)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events