WO2017076990A1 - Sels d'addition de n-[4-(4-{[(1s)-1-(5-méthyl-4-oxo-3-phényl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)éthyl]amino}-7h-pyrrolo[2,3-d]pyrimidin-5-yl)-1h-indol-6-yl]sulfamide - Google Patents

Sels d'addition de n-[4-(4-{[(1s)-1-(5-méthyl-4-oxo-3-phényl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)éthyl]amino}-7h-pyrrolo[2,3-d]pyrimidin-5-yl)-1h-indol-6-yl]sulfamide Download PDF

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WO2017076990A1
WO2017076990A1 PCT/EP2016/076594 EP2016076594W WO2017076990A1 WO 2017076990 A1 WO2017076990 A1 WO 2017076990A1 EP 2016076594 W EP2016076594 W EP 2016076594W WO 2017076990 A1 WO2017076990 A1 WO 2017076990A1
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methyl
indol
oxo
dihydropyrrolo
sulfamide
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PCT/EP2016/076594
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Francesc Carrera Carrera
Miquel DEL TORO CARRION
Monserrat Erra Sola
Juan Bautista Perez Garcia
Maria Carme SERRE COMA
Enrique Moyes Valls
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Almirall, S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

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  • the present invention is directed to novel crystalline, stable and pharmaceutically acceptable, addition salts of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide with sulfonic acid derivatives, in particular with methanesulfonic acid, ethanesulfonic acid and benzenesulfonic acid, or pharmaceutically acceptable solvates thereof.
  • the invention is also directed to pharmaceutical compositions comprising the salts, methods of using them to treat respiratory diseases associated with inhibition of Phosphoinositide 3-Kinase (PI3K), and processes and intermediates useful for preparing such salts.
  • PI3K Phosphoinositide 3-Kin
  • WO 2014/060432 discloses pyrrolotriazinone derivatives as potent PI3Ks inhibitors. Although these compounds have shown adequate pharmacological activity, some of the compounds exemplified in this International Patent Application present a complex polymorphic landscape with numerous crystalline forms, and many of these compounds cannot be formulated for effective delivery by inhalation as a dry powder. Delivery by inhalation as a dry powder is challenging. It requires careful control of the particle size of the powder which is to be inhaled, and careful control of the particle size distribution. Further, it is important to avoid particle agglomeration or aggregation.
  • PI3Ks inhibitors which are physically and chemically stable, with relative high melting point and which do not exhibit polymorphism. This would allow the material to be further manipulated, e.g. by drying, milling or by micronization without significant decomposition, loss of crystallinity or exhibiting any change in polymorphism to prepare pharmaceutical compositions and formulations.
  • the present invention provides pharmaceutically acceptable crystalline addition salts of A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide with sulfonic acid derivatives selected from methanesulfonic acid, ethanesulfonic acid and benzenesulfonic acid, and pharmaceutically acceptable solvates thereof.
  • the invention also provides a pharmaceutical composition comprising a salt of the invention and a pharmaceutically acceptable carrier.
  • the invention further provides pharmaceutical compositions as defined above and a therapeutically effective amount of one or more other therapeutic agents.
  • the invention further provides combinations comprising a salt of the invention and a therapeutically effective amount of one or more other therapeutic agents.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibition of Phosphoinositide 3-Kinase (PI3K), in particular wherein the pathological condition or disease is a respiratory disease; more in particular wherein the pathological condition or disease is selected from asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis and sarcoidosis; comprising administering a therapeutically effective amount of a salt of the invention.
  • COPD chronic obstructive pulmonary disease
  • cystic fibrosis cystic fibrosis
  • bronchiectasis bronchiectasis
  • cough idiopathic pulmonary fibrosis
  • sarcoidosis comprising administering a therapeutically effective amount of a salt of the invention.
  • PI3K Phosphoinositide 3-Kinase
  • a therapeutically effective amount of a pharmaceutical composition comprising a salt of the invention and a pharmaceutically-acceptable carrier, or a pharmaceutical composition comprising a salt of the invention, a pharmaceutically- acceptable carrier and a therapeutically effective amount of one or more other therapeutic agents.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibition of Phosphoinositide 3-Kinase (PI3K), in particular wherein the pathological condition or disease is as defined before, comprising
  • the invention also provides a salt of the invention as described herein, a pharmaceutical composition comprising a salt of the invention and a pharmaceutically acceptable carrier, a pharmaceutical composition as defined above together with a therapeutically effective amount of one or more other therapeutic agents or combination of a salt of the invention together with a therapeutically effective amount of one or more other therapeutic agents, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Phosphoinositide 3-Kinase (PI3K); in particular wherein the pathological condition or disease is a respiratory disease; more in particular wherein the pathological condition or disease is selected from asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis and sarcoidosis.
  • COPD chronic obstructive pulmonary disease
  • the invention also provides the use of the salt of the invention, a pharmaceutical composition comprising a salt of the invention and a pharmaceutically acceptable carrier, a pharmaceutical composition as defined above together with a therapeutically effective amount of one or more other therapeutic agents or a combination of a salt of the invention together with one or more other therapeutic agents, for the manufacture of a formulation or medicament for treating the above mentioned pathological conditions or diseases.
  • Figure 1 illustrates the X-Ray Powder Diffraction (XRPD) diffractogram of A/-[4-(4- ⁇ [(1 S)-1- (5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide methanesulfonate.
  • XRPD X-Ray Powder Diffraction
  • Figure 2 illustrates the Differential Scanning Calorimetry (DSC) thermogram of ⁇ /-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ - 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide methanesulfonate.
  • DSC Differential Scanning Calorimetry
  • FIG. 3 illustrates the Gravimetric Vapour Sorption (GVS) isotherm of A/-[4-(4- ⁇ [(1 S)-1 -(5- methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide methanesulfonate.
  • GVS Gravimetric Vapour Sorption
  • Figure 4 illustrates the Proton Nuclear Magnetic Resonance ( 1 H-NMR) spectrum of ⁇ /-[4- (4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide methanesulfonate.
  • Figure 5 illustrates the X-Ray Powder Diffraction (XRPD) diffractogram of A/-[4-(4- ⁇ [(1 S)-1- (5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide ethanesulfonate.
  • XRPD X-Ray Powder Diffraction
  • Figure 6 illustrates the Differential Scanning Calorimetry (DSC) thermogram of ⁇ /-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ - 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide ethanesulfonate.
  • DSC Differential Scanning Calorimetry
  • FIG. 7 illustrates the Gravimetric Vapour Sorption (GVS) isotherm of A/-[4-(4- ⁇ [(1 S)-1 -(5- methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide ethanesulfonate.
  • GVS Gravimetric Vapour Sorption
  • Figure 8 illustrates the Proton Nuclear Magnetic Resonance ( 1 H-NMR) spectrum of ⁇ /-[4- (4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide ethanesulfonate.
  • Figure 9 illustrates the X-Ray Powder Diffraction (XRPD) diffractogram of A/-[4-(4- ⁇ [(1 S)-1- (5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide ethanesulfonate type A polymorph.
  • XRPD X-Ray Powder Diffraction
  • Figure 10 illustrates the X-Ray Powder Diffraction (XRPD) diffractogram of A/-[4-(4- ⁇ [(1 S)- 1 -(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide ethanesulfonate type B polymorph.
  • XRPD X-Ray Powder Diffraction
  • Figure 1 1 illustrates the X-Ray Powder Diffraction (XRPD) overlapped diffractogram of the type A and type B polymorphs of A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide ethanesulfonate.
  • XRPD X-Ray Powder Diffraction
  • Figure 12 illustrates the X-Ray Powder Diffraction (XRPD) diffractogram of A/-[4-(4- ⁇ [(1 S)- 1 -(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide benzenesulfonate.
  • XRPD X-Ray Powder Diffraction
  • Figure 13 illustrates the Differential Scanning Calorimetry (DSC) thermogram of ⁇ /-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ - 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide benzenesulfonate.
  • DSC Differential Scanning Calorimetry
  • FIG 14 illustrates the Gravimetric Vapour Sorption (GVS) isotherm of A/-[4-(4- ⁇ [(1 S)-1- (5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide benzenesulfonate.
  • GVS Gravimetric Vapour Sorption
  • Figure 15 illustrates the Proton Nuclear Magnetic Resonance ( 1 H-NMR) spectrum of ⁇ /-[4- (4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide benzenesulfonate.
  • terapéuticaally effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes:
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, i.e. a salt of the invention or a pharmaceutically-acceptable salt thereof, and one or more molecules of a solvent.
  • solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent.
  • Representative solvents include by way of example, water, ethanol, isopropanol and the like. When the solvent is water, the solvate formed is a hydrate.
  • co-crystal refers to a solid that is crystalline single phase material composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts.
  • pharmaceutically (or physiologically) acceptable carrier (or diluent) refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • One embodiment of the present invention refers to a pharmaceutically acceptable crystalline addition salt of A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide with sulfonic acid derivatives selected from methanesulfonic acid, ethanesulfonic acid and benzenesulfonic acid, or pharmaceutically acceptable solvates thereof.
  • the addition salt is A/-[4-(4- ⁇ [(1S)-1-(5- methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2, 1 -f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide methanesulfonate, or pharmaceutically acceptable solvates thereof.
  • methanesulfonate contains 1 molar equivalent of A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4-oxo-3- phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin- 5-yl)-1 H-indol-6-yl]sulfamide per molar equivalent of the methanesulfonic acid.
  • methanesulfonic acid (CAS RN 75-75-2) is a colourless liquid with the molecular formula CH4O3S (molecular weight of 96.11 g/mol).
  • Salts of methanesulfonic acid are known as methanesulfonates, mesilates (International Nonproprietary Name or INN) or mesylates (United States Adopted Name or USAN).
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide methanesulfonate has an XRPD pattern with at least one peak at 2 ⁇ of 22.3 ⁇ 0.1.
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide methanesulfonate has an XRPD pattern comprising peaks at 2 ⁇ of 8.1 ⁇ 0.1, 9.6 ⁇ 0.1, 13.1+0.1 , 15.9 ⁇ 0.1, 16.6 ⁇ 0.1, 17.5 ⁇ 0.1, 19.1+0.1, 22.3 ⁇ 0.1, 22.8 ⁇ 0.1, 23.5 ⁇ 0.1, 24.1 ⁇ 0.1 and24.6 ⁇ 0.1.
  • ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide methanesulfonate has an XRPD pattern comprising peaks at 2 ⁇ of 8.1+0.1 , 8.7 ⁇ 0.1, 9.6 ⁇ 0.1, 10.1+0.1 , 10.4 ⁇ 0.1, 11.2+0.1 , 12.1+0.1, 12.2 ⁇ 0.1, 13.1+0.1, 13.5 ⁇ 0.1, 15.3 ⁇ 0.1, 15.9 ⁇ 0.1, 16.0 ⁇ 0.1, 16.6 ⁇ 0.1, 16.7 ⁇ 0.1 ,17.5 ⁇ 0.1, 17.7 ⁇ 0.1, 18.4 ⁇ 0.1, 19.1+0.1 , 19.6 ⁇ 0.1, 20.6 ⁇ 0.1, 20.8 ⁇ 0.1, 21.8 ⁇ 0.1, 22.3 ⁇ 0.1 , 22.8 ⁇ 0.1 , 23.2 ⁇ 0.1 , 23.5 ⁇ 0.1 , 24.1 ⁇ 0.1 , 24.6 ⁇ 0.1 , 25.5 ⁇ 0.1 , 26.0 ⁇ 0.1 , 26.7 ⁇ 0.1 , 28.2 ⁇ 0.1 , 28.7 ⁇ 0.1 , 30.1 ⁇ 0.1 , 30.6 ⁇ 0.1 , 31.9 ⁇ 0.1
  • ⁇ pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide methanesulfonate has an XRPD pattern substantially as shown in Figure 1.
  • the addition salt is A/-[4-(4- ⁇ [(1 S)-1 -(5- methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide ethanesulfonate, or pharmaceutically acceptable solvates thereof.
  • A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin- 2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide ethanesulfonate contains 1 molar equivalent of A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide per molar equivalent of the ethanesulfonic acid.
  • ethanesulfonic acid (CAS RN 594-45-6) is a colourless liquid with the molecular formula C2H6O3S (molecular weight of 1 10.13 g/mol).
  • Salts of ethanesulfonic acid are known as ethanesulfonates, esilates (International Nonproprietary Name or INN) or esylates (United States Adopted Name or USAN).
  • the A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide ethanesulfonate has an XRPD pattern with at least one peak at 2 ⁇ of 7.3 ⁇ 0.1.
  • the A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -/][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide ethanesulfonate has an XRPD pattern with at least one peak at 2 ⁇ of 19.5 ⁇ 0.1 .
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate has an XRPD pattern comprising peaks at 2 ⁇ of 7.3 ⁇ 0.1, 8.7 ⁇ 0.1, 8.9 ⁇ 0.1, 10.0 ⁇ 0.1, 12.8 ⁇ 0.1, 15.9 ⁇ 0.1, 19.2 ⁇ 0.1, 19.5 ⁇ 0.1, 20.1 ⁇ 0.1, 21.5 ⁇ 0.1, 21.7 ⁇ 0.1, 22.2 ⁇ 0.1, 23.2 ⁇ 0.1, 23.4 ⁇ 0.1, 24.0 ⁇ 0.1 and 25.4 ⁇ 0.1.
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate has an XRPD pattern comprising peaks at 2 ⁇ of 7.3 ⁇ 0.1, 8.7 ⁇ 0.1, 8.9 ⁇ 0.1, 10.0 ⁇ 0.1, 10.6 ⁇ 0.1, 11.7+0.1, 12.1+0.1 , 12.8 ⁇ 0.1, 13.6 ⁇ 0.1, 14.2 ⁇ 0.1, 15.1+0.1 , 15.9 ⁇ 0.1, 16.8 ⁇ 0.1, 17.7 ⁇ 0.1, 19.2 ⁇ 0.1, 19.5 ⁇ 0.1, 20.1+0.1, 21.5+0.1, 21.1+0.1, 21.7+0.1, 22.2+0.1, 23.2+0.1, 2
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate has an XRPD pattern substantially as shown in Figure 5.
  • the addition salt is A/-[4-(4- ⁇ [(1S)-1-(5- methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate type A polymorph, or pharmaceutically acceptable solvates thereof.
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate type A polymorph has an XRPD pattern comprising peaks at 2 ⁇ of 7.5 ⁇ 0.1, 7.6 ⁇ 0.1, 8.9 ⁇ 0.1, 9.2 ⁇ 0.1, 10.5 ⁇ 0.1, 11.6+0.1 , 12.7 ⁇ 0.1, 15.1+0.1 , 15.8 ⁇ 0.1, 16.6 ⁇ 0.1, 17.6 ⁇ 0.1, 18.5 ⁇ 0.1, 19.0 ⁇ 0.1, 19.5 ⁇ 0.1, 22.0 ⁇ 0.1, 22.4 ⁇ 0.1, 23.5 ⁇ 0.1, 24.1 ⁇ 0.1, 25.3 ⁇ 0.1, 26.3 ⁇ 0.1, 27.0 ⁇ 0.1, 28.
  • a polymorph has an XRPD pattern substantially as shown in Figure 9.
  • the addition salt is A/-[4-(4- ⁇ [(1S)-1-(5- methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate type B polymorph, or pharmaceutically acceptable solvates thereof.
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl- 4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate type B polymorph has an XRPD pattern with at least one peak at 2 ⁇ of 9.9 ⁇ 0.1.
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl- 4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate type B polymorph has an XRPD pattern with at least one peak at 2 ⁇ of 9.9 ⁇ 0.1 , and does not have a peak at 2 ⁇ of 7.6 ⁇ 0.1.
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate type B polymorph has an XRPD pattern with at least two peaks at 2 ⁇ of 9.9 ⁇ 0.1 and 20.0 ⁇ 0.1, and does not have peaks at 2 ⁇ of 7.5 ⁇ 0.1 and 7.6 ⁇ 0.1.
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate type B polymorph has an XRPD pattern comprising peaks at 2 ⁇ of 8.5 ⁇ 0.1, 9.9 ⁇ 0.1, 12.7 ⁇ 0.1, 16.7 ⁇ 0.1, 17.7 ⁇ 0.1, 19.5 ⁇ 0.1, 20.0 ⁇ 0.1, 21.7 ⁇ 0.1 , 23.3 ⁇ 0.1 and 27.2 ⁇ 0.1.
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate type B polymorph has an XRPD pattern comprising peaks at 2 ⁇ of 8.5 ⁇ 0.1, 9.9 ⁇ 0.1, 11.1+0.1 , 12.7 ⁇ 0.1, 13.5 ⁇ 0.1, 14.0 ⁇ 0.1, 14.3 ⁇ 0.1, 16.7 ⁇ 0.1, 17.7 ⁇ 0.1, 19.5 ⁇ 0.1, 20.0 ⁇ 0.1, 21.7 ⁇ 0.1, 22.1 ⁇ 0.1, 22.5 ⁇ 0.1, 23.3 ⁇ 0.1, 24.1 ⁇ 0.1, 25.5 ⁇ 0.1, 25.8 ⁇ 0.1, 26.6 ⁇ 0.1, 27.2 ⁇ 0.1 and 28.1 ⁇ 0.1.
  • the ⁇ /-[4-(4- ⁇ [(1 S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide ethanesulfonate type B polymorph has an XRPD pattern substantially as shown in Figure 10.
  • the addition salt is A/-[4-(4- ⁇ [(1S)-1-(5- methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide benzenesulfonate, or pharmaceutically acceptable solvates thereof.
  • benzenesulfonate contains 1 molar equivalent of A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4-oxo-3- phenyl-3,4-dihydropyrrolo[2 -f][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin- 5-yl)-1 H-indol-6-yl]sulfamide per molar equivalent of the benzenesulfonic acid.
  • benzenesulfonic acid (CAS RN 98-11-3) is a solid at 20°C with the molecular formula C6H6O3S (molecular weight of 158.18 g/mol). Salts of benzenesulfonic acid are known as benzenesulfonates, besilates (International Nonproprietary Name or INN) or besylates (United States Adopted Name or USAN).
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide benzenesulfonate has an XRPD pattern with at least one peak at 2 ⁇ selected of 19.5 ⁇ 0.1.
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide benzenesulfonate has an XRPD pattern comprising peaks at 2 ⁇ of 6.7 ⁇ 0.1, 8.5 ⁇ 0.1, 12.9 ⁇ 0.1, 13.7 ⁇ 0.1, 16.6 ⁇ 0.1, 19.5 ⁇ 0.1, 20.3 ⁇ 0.1 , 20.7 ⁇ 0.1 , 21.9 ⁇ 0.1 , 22.8 ⁇ 0.1 , 23.5 ⁇ 0.1 , 24.9 ⁇ 0.1 , 26.4 ⁇ 0.1 and 27.6 ⁇ 0.1.
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide benzenesulfonate has an XRPD pattern comprising peaks at 2 ⁇ of 6.7 ⁇ 0.1 , 8.5 ⁇ 0.1 , 10.5 ⁇ 0.1, 12.5 ⁇ 0.1, 12.9 ⁇ 0.1, 13.7 ⁇ 0.1, 14.6 ⁇ 0.1, 15.5 ⁇ 0.1, 16.6 ⁇ 0.1, 17.0 ⁇ 0.1, 18.7 ⁇ 0.1, 19.5 ⁇ 0.1, 20.3 ⁇ 0.1, 20.7 ⁇ 0.1, 21.9 ⁇ 0.1, 22.8 ⁇ 0.1, 23.5 ⁇ 0.1, 24.9 ⁇ 0.1, 26.4 ⁇ 0.1, 27.6 ⁇ 0.1, 26.8 ⁇ 0.1, 29.3 ⁇
  • the A/-[4-(4- ⁇ [(1S)-1-(5-methyl-4- oxo-3-phenyl-3,4-dihydropyrrolo[2,1-/][1,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3- ⁇ pyrimidin-5-yl)-1H-indol-6-yl]sulfamide benzenesulfonate has an XRPD pattern substantially as shown in Figure 12.
  • the invention also encompasses pharmaceutical compositions comprising a
  • the salts of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Processes for preparing salts of the invention are provided as further embodiments of the invention and are illustrated by the procedures below.
  • the salt of the invention can be synthesized from A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3- phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin- 5-yl)-1 H-indol-6-yl]sulfamide and methanesulfonic acid, ethanesulfonic acid or
  • benzenesulfonic acid which are commercially available from, for example, Scharlau or Sigma-Aldrich.
  • Suitable solvents for carrying out the reaction can be selected by a skilled chemist and may depend on the specific salt to be formed. Mixtures of appropriate solvents may be used, optionally containing water. For example, the appropriate solvents may be selected from methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, water or a mixture thereof.
  • the salt can be isolated from the reaction mixture by any conventional means such as precipitation, concentration, centrifugation and the like.
  • a salt of the invention typically contains between about 0.60 and 1.20 molar equivalents of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 -f][1 ,2,4]triazin-2- yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-yl]sulfamide per molar equivalent of the acid, more typically 0.85 and 1.15 molar equivalents of A/-[4-(4- ⁇ [(1 S)-1- (5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-indol-6-y
  • molar ratios described in the methods of the invention can be readily determined by various methods available to those skilled in the art. For example, such molar ratios can be readily determined by 1 H-NMR. Alternatively, elemental analysis and HPLC methods can be used to determine the molar ratio.
  • benzenesulfonic acid had the required properties for dry powder inhalation.
  • the instrument is performance checked using a certified Corundum standard (NIST 1976).
  • the software used for data collection was Diffrac Commander v3.0 and the data were analysed and presented using Diffrac.EVA v4.0.
  • XRPD angle values may vary in the range ⁇ 1 on the last decimal place.
  • the measured relative intensities vs. the strongest peak are given as very strong (vs) above 50%, as strong (s) between 25 and 50%, as medium (m) between 10 and 25%, as weak (w) between 5 and 10% and as very weak (vw) under 5% relative peak height.
  • the XRPD intensities may vary between different samples and different sample preparations for a variety of reasons including preferred orientation. It will also be appreciated by a person skilled in the art that smaller shifts in the measured Angle may occur for a variety of reasons including variation of sample surface level in the diffractometer.
  • the differential scanning calorimetry (DSC) thermograms were obtained using a Mettler Toledo Instrument DSC1 STARe System equipped with a 34 position auto-sampler. Data were analysed and presented using STARe Software v12.10b. The calibration for energy and temperature was carried out using certified indium and zinc. Typically 0.5 - 3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 300 °C (some runs up to 400°C). A purge of dry nitrogen at 50 ml/min was maintained over the sample. DSC values may vary in the range ⁇ 2 on the last decimal place.
  • TGA/SDTA 851 e system equipped with a 34 position autosampler. Data were analysed and presented using STARe Software v12.10b The instrument was temperature calibrated using certified Aluminium and Zinc and loss on drying was calibrated using and standard of Calcium Oxalate Monohydrate. Typically 1 - 10 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from room temperature to 400°C. A nitrogen purge at 60 ml/min was maintained over the sample.
  • GVS Gravimetric Vapour Sorption
  • DVS Dynamic Vapour Sorption
  • the sample temperature was maintained at 25°C by the instrument controls.
  • the humidity was controlled by mixing streams of dry and wet nitrogen.
  • the relative humidity (RH) was measured by a calibrated Rotronic probe (dynamic range of 1.0 - 100 %RH), located near the sample.
  • the weight change (mass relaxation) of the sample as a function of %RH was constantly monitored by the microbalance (accuracy ⁇ 0.005 mg).
  • the microbalance was calibrated with weights of 20 and 200 mg and the relative humidity was calibrated with 10%, 50% and 80% RH standards and at 25°C and 40°C.
  • sample typically 5 - 20 mg were placed in a tared mesh stainless steel basket under ambient conditions.
  • the sample was loaded and unloaded at 40 %RH and 25 °C (typical room conditions).
  • a moisture sorption isotherm was performed as outlined below (4 scans giving 2 complete cycles).
  • the standard isotherm was performed at 25°C at 10% RH intervals over a 0 - 90% RH range.
  • the sample was stirred (500 rpm) at 50°C for 1 hour. The sample was then slowly cooled to 5°C at 0.1 °C/min and held at 5°C overnight. The solid formed was matured (50°C/5°C, cycles of 8h) for a week. The sample was filtered and then dried in a vacuum oven at 50°C for 2 days.
  • the 1 H-NMR spectra of the sample obtained confirmed the 1 :1 stoichiometry of the solid.
  • Figure 1 illustrates the XRPD diffractogram of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl- 3,4-dihydropyrrolo[2 - ⁇ [1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide methanesulfonate.
  • the sample exhibits a good crystallinity.
  • Figure 2 illustrates the DSC thermogram of A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide methanesulfonate.
  • the sample exhibits a characteristic high endotherm at onset 195.6°C ( ⁇ 0.2°C) followed by melting and decomposition. This behaviour confirms high stability of the sample until more than 185°C.
  • Figure 3 illustrates the GVS isotherm of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide methanesulfonate. Mass change was approx. 2% from 0-80% RH.
  • Figure 4 corresponds to the 1 H-NMR spectrum of the methanesulfonate salt.
  • the sample was stirred (500 rpm) at 50°C for 1 hour.
  • the sample was then slowly cooled to 5°C at 0.1 °C/min and then warmed up to 50°C at the same speed. These cycles of 8h were repeated for 4 days.
  • the solid formed was filtered and then dried in a vacuum oven at 50°C for 2 days.
  • the 1 H-NMR spectra of the sample obtained confirmed the 1 :1 stoichiometry of the solid with no residual solvents.
  • Figure 5 illustrates the XRPD diffractogram of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl- 3,4-dihydropyrrolo[2 - ⁇ [1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide ethanesulfonate.
  • the sample exhibits a good crystallinity.
  • Figure 6 illustrates the DSC thermogram of A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide ethanesulfonate.
  • the sample exhibits a characteristic high endotherm at onset 107.9°C ( ⁇ 0.2°C) and 180.0°C ( ⁇ 0.2°C). This confirms the high stability of the sample until more than 100°C.
  • Figure 7 illustrates the GVS isotherm of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide ethanesulfonate.
  • Mass change was approx. 3.5% from 0-80% RH. This water sorption was reversible and no hydrates were formed during the GVS process.
  • Figure 8 corresponds to the 1 H-NMR spectrum of the ethanesulfonate salt. It clearly shows a stoichiometry ratio of 1 :1 free base / ethanesulfonic acid, as inferred from the comparison between the integral values of the protons corresponding to the CH3- group of ethanesulfonate and a methyl group of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2,1 - ⁇ [1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7/-/-pyrrolo[2,3-c ]pyrimidin-5-yl)-1 /-/- indol-6-yl]sulfamide.
  • the 1 H NMR spectra of the sample obtained confirmed the 1 :1 stoichiometry of the solid with no residual solvents.
  • Figure 9 illustrates the XRPD diffractogram of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl- 3,4-dihydropyrrolo[2,1-f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide ethanesulfonate type A polymorph. The sample exhibits a good crystallinity.
  • polymorph A 1 H-indol-6-yl]sulfamide ethanesulfonate type B polymorph Method 1 : 0.5 g of the product obtained above (polymorph A) are stirred in 1 .5 mL of Methanol for 5 days, and then filtered. After drying in a vacuum oven at 50°C, polymorph B is obtained.
  • Method 2 10 g of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1 - /][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-c ]pyrimidin-5-yl)-1 /-/-indol-6-yl]sulfamide were dissolved at 50°C in a mixture of 150 mL of isopropanol, 150 mL of methanol and 3 mL of water. Then 1 .91 g of ethanesulfonic acid were added dropwise.
  • the 1 H NMR spectra of the sample obtained confirmed the 1 :1 stoichiometry of the solid with no residual solvents.
  • Figure 10 illustrates the XRPD diffractogram of A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4-oxo-3-phenyl- 3,4-dihydropyrrolo[2,1- ⁇ [1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide ethanesulfonate type B polymorph.
  • the sample exhibits a good crystallinity.
  • the sample was stirred (500 rpm) at 50°C for 1 hour.
  • the sample was then slowly cooled to 5°C at 0.1 °C/min and then warmed up to 50°C at the same speed. These cycles of 8h were repeated for 4 days.
  • the solid formed was filtered and then dried in a vacuum oven at 50°C for 2 days.
  • the 1 H-NMR spectra of the sample obtained confirmed the 1 :1 stoichiometry of the solid.
  • Figure 12 illustrates the XRPD diffractogram of A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4-oxo-3-phenyl- 3,4-dihydropyrrolo[2 - ⁇ [1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide benzenesulfonate.
  • the sample exhibits a good crystallinity.
  • Figure 13 illustrates the DSC thermogram of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl- 3,4-dihydropyrrolo[2 - ⁇ [1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-aGpyrimidin-5-yl)-1 H- indol-6-yl]sulfamide benzenesulfonate.
  • the sample exhibits a characteristic high endotherm at onset 170.6°C ( ⁇ 0.2°C). This confirms the high stability of the sample until more than 160°C.
  • Figure 14 illustrates the GVS isotherm of A/-[4-(4- ⁇ [(1 S)-1-(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2 -f][1 ,2,4]triazin-2-yl)ethyl]amino ⁇ -7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H- indol-6-yl]sulfamide benzenesulfonate.
  • Mass change was approx. 5% from 0-80% RH.
  • Figure 15 corresponds to the 1 H-NMR spectrum of the benzenesulfonate salt. It clearly shows a stoichiometry ratio of 1 :1 free base / benzenesulfonic acid, as inferred from the comparison between the integral values of the protons corresponding to benzene group of benzenesulfonate and a methyl group of A/-[4-(4- ⁇ [(1 S)-1 -(5-methyl-4-oxo-3-phenyl-3,4- dihydropyrrolo[2,1-/][1 ,2,4]triazin-2-yl ⁇
  • the salts of the present invention displayed good thermal behaviour, are not hygroscopic, had a relatively high melting point and showed appropriate XRPD pattern before and after GVS determination (no change in form or crystallinity).
  • the pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient(s) into association with the carrier. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Formulations generally comprise a powder mix for inhalation of the salt of the invention and a suitable powder base (carrier substance) such as starch or a pharmaceutically acceptable sugar, such as lactose or glucose. Use of lactose is preferred.
  • the powder base may include additional components such as preservatives, stabilizing agents, absorption enhancers or aerodynamic modifier.
  • Each capsule or cartridge may generally contain between 0.1 ⁇ g and 9000 ⁇ g of each therapeutically active ingredient. Alternatively, the active ingredient (s) may be presented without excipients.
  • Packaging of the formulation may be suitable for unit dose or multi-dose delivery.
  • the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices.
  • the formulation is administered by a multi- dose device.
  • Multi-dose inhalers do not contain pre-measured quantities of the powder formulation. They consist of a relatively large container and a dose measuring principle that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement.
  • Various dose measuring principles exist, including rotatable membranes (e. g. EP0069715) or disks (e. g. GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (e. g. EP 0166294; GB 2165159 and WO 92/09322) and rotatable frustums (e. g.
  • WO 92/00771 all having cavities which have to be filled with powder from the container.
  • Other multi dose devices have measuring plungers with a local or circumferential recess to displace a certain volume of powder from the container to a delivery chamber or an air conduit (e. g. EP 0505321 , WO 92/04068 and WO 92/04928), or measuring slides such as the Genuair® devise (formerly known as Novolizer SD2FL) which is described in the following patent applications: WO 97/000703, WO 03/000325 and WO2006/008027.
  • Formulation Example 1 Formulation Example 1 (Formulation for inhalation with a DPI)
  • the salts of the invention may also be combined with a therapeutically effective amount of one or more other therapeutic agents useful in the treatment or prevention of pathological conditions or diseases susceptible to amelioration by inhibition of Phosphoinositide 3- Kinase (PI3K).
  • PI3K Phosphoinositide 3- Kinase
  • the combinations of the invention can optionally comprise a therapeutically effective amount one or more additional active substances which are known to be useful in the treatment of respiratory diseases, such as: (a) corticosteroids and glucocorticoids; (b) antihistamines; (c) chemokine receptor antagonists; (d) chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) antagonist; (e) leukotriene receptor antagonists; (f) Janus kinase (JAK) inhibitors; (g) Spleen tyrosine kinase (Syk) inhibitors; (h) Phosphosdiesterase (PDE) IV inhibitors; (i) p38 Mitogen-Activated Protein Kinase (p38 MAPK) Inhibitors; (j) Anticholinergic agents; (k) Beta adrenergic agonists; (I) MABA (molecules with dual activity: beta-adrenergic agonists and muscarinic receptor antagonist; (m)
  • each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
  • the active ingredients may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. Preferably, the active ingredients are administered once or twice a day.
  • suitable corticosteroids and glucocorticoids that can be combined with salt compound of the present invention are prednisolone, methylprednisolone,
  • dexamethasone dexamethasone cipecilate, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone
  • prednicarbate alclometasone dipropionate, halometasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, butixocort propionate, deprodone propionate, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone,
  • betamethasone 17-valerate betamethasone, betamethasone dipropionate,
  • hydrocortisone acetate hydrocortisone sodium succinate
  • Suitable anti-histamines that can be combined with the salts of the invention are methapyrilene, mequitazine, azelastine hydrochloride, acrivastine, emedastine difumarate, emedastine fumarate, loratadine, cyproheptadine hydrochloride,
  • diphenhydramine hydrochloride doxepin hydrochloride, promethazine hydrochloride, levocabastine hydrochloride, desloratadine, cinnarizine, setastine hydrochloride, mizolastine, ebastine, cetirizine hydrochloride, epinastine hydrochloride, olopatadine hydrochloride, bepotastine besilate, triprolidine hydrochloride, rupatadine fumarate, fexofenadine hydrochloride, levocetirizine dihydrochloride, ketotifen, azatadine maleate, dimethindene maleate, clemastine fumarate, alcaftadine, bilastine, vapitadine
  • hydrochloride AZD-1744, GSK-1004723D, GSK-835726 or SUN-1334H.
  • chemokine receptor antagonists that can be combined with the salts of the invention are maraviroc or enfuvirtide.
  • suitable CRTH2 antagonist that can be combined with the salts of the present invention are ramatroban, AMG-009, OC-000459, AZD-1981 , ACT-129968 or QAV-680.
  • Suitable leukotriene antagonist that can be combined with the salts of the present invention are CYSLTR1 antagonists, such as montelukast, pranlukast or zafirlukast; or CYSLTR2 antagonists, such as pranlukast, zafirlukast or tipilukast.
  • CYSLTR1 antagonists such as montelukast, pranlukast or zafirlukast
  • CYSLTR2 antagonists such as pranlukast, zafirlukast or tipilukast.
  • JAK inhibitors that can be combined with the salt of the present invention are tofacitinib, ruxolitinib, baricitinib, decernotinib, filgotinib, peficitinib, INCB- 0391 10, INCB-047986, ABT-494, INCB-047986 or ACM 10.
  • Suitable Syk kinase inhibitors that can be combined with the salts of the present invention are fosfamatinib (from Rigel), R-348 (from Rigel), R-343 (from Rigel), R- 1 12 (from Rigel), piceatannol, 2-(2-Aminoethylamino)-4-[3-(trifluoromethyl)phenylamino] pyrimidine-5-carboxamide, R-091 (from Rigel), 6-[5-Fluoro-2-(3,4,5- trimethoxyphenylamino)pyrimidin-4-ylamino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2- b][1 ,4]oxazin-3-one benzenesulfonate (R-406 from Rigel), 1 -(2,4,6-Trihydroxyphenyl)-2- (4-methoxyphenyl)ethan-1 -one, N-[4-[6-(Cyclobut
  • PDE4 inhibitors examples include benafentrine dimaleate, etazolate, denbufylline, rolipram, cipamfylline, zardaverine, arofylline, filaminast, tipelukast, tofimilast, piclamilast, tolafentrine, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast, oglemilast, apremilast, tetomilast, filaminast, (R)-(+)-4-[2-(3-Cyclopentyloxy-4- methoxyphenyl)-2-phenylethyl]pyridine (CDP-840), N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4- fluorobenzyl)-5-hydroxy-1 H-in
  • Example of suitable p38 MAPK inhibitor that can be combined with salt compounds of the present invention is ARRY-797.
  • M3 antagonists anticholinergics
  • salt compounds of the present invention examples include tiotropium, umeclidinium, aclidinium,
  • glycopyrrolate or ipratropium
  • beta adrenergic agonists examples include salmeterol, formoterol, arformoterol, indacaterol, vilanterol, abediterol or olodaterol.
  • suitable MABA compounds that can be combined with salt compounds of the present invention are batefenterol, LAS190792, LAS191351 or TEI-3252.
  • Example of suitable PKC inhibitor that can be combined with salt compounds of the present invention is NVP-AEB071.
  • FLAP inhibitors examples include MK886 or BAY X 1005.
  • Example of suitable 5-LO inhibitor that can be combined with salt compounds of the present invention is WY-50295T.
  • Example of suitable CysLT receptor antagonists that can be combined with salt compounds of the present invention is montelukast.
  • Example of suitable thromboxane A2 antagonists that can be combined with salt compounds of the present invention is ramatroban.
  • Example of suitable DP1 receptor antagonists that can be combined with salt compounds of the present invention is laropiprant.
  • Example of suitable DP1 receptor agonists that can be combined with salt compounds of the present invention is BW-245C.
  • Example of suitable IP receptor agonists that can be combined with salt compounds of the present invention is RO-1 138452.
  • Example of suitable Anti-lgE that can be combined with salt compounds of the present invention is omalizumab.
  • Example of suitable IL5 antibody that can be combined with salt compounds of the present invention is mepolizumab.
  • decongestants examples include ephedrine, levo-methamphetamine, naphazoline, oxymetazoline, phenylephrine, phenylpropanolamine, propylhexedrine, pseudoephedrine, synephrine or tetrahydrozoline.
  • mucolytics examples include acetylcysteine, ambroxol, bromhexine, carbocisteine, domiodol, eprazinone, erdosteine, letosteine, neltenexine, sobrerol, stepronin or tiopronin.
  • Example of suitable antitussives that can be combined with salt compounds of the present invention is dextromethorphan.
  • suitable analgesics that can be combined with salt compounds of the present invention are aspirin, paracetamol, rofecoxid, celecoxib, morphine, codeine, oxycodone, hydrocodone, dihydromorphine or flupirtine.
  • Suitable expectorants that can be combined with salt compounds of the present invention are antimony pentasulfide, guaiacolsulfonate, guaifenesin, potassium iodide or tyloxapol.
  • PI3K phosphoinositide 3-kinase activity
  • the salts of the invention, pharmaceutical compositions and the combinations of the invention may be used in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Phosphoinositide 3-Kinase (PI3K), typically respiratory diseases.
  • the respiratory disease is preferably one selected from asthma, Chronic Obstructive Pulmonary Disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis and sarcoidosis. Asthma or chronic obstructive pulmonary disease are more preferred.
  • the active compound in the combination and the other therapeutic agent(s) as defined above may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
  • all active agents would be administered at the same time, or very close in time.
  • one or two actives could be taken in the morning and the other(s) later in the day.
  • one or two actives could be taken twice daily and the other(s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately.
  • at least two, and more preferably all, of the actives would be taken together at the same time.
  • at least two, and more preferably all actives would be administered as an admixture.
  • compositions according to the invention are preferably administered in the form of compositions for inhalation delivered with the help of inhalers, especially dry powder inhalers, however, any other form or parenteral or oral application is possible.
  • inhaled compositions embodies the preferred application form, especially in the therapy of chronic obstructive pulmonary disease or for the treatment of asthma.

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Abstract

La présente invention concerne des sels d'addition cristallins de (I) N-[4-(4-{[(1S)-1-(5-méthyl-4-oxo-3-phényl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)éthyl]amino}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indol-6-yl]sulfamide avec des dérivés acides sulfoniques, choisis parmi l'acide méthanesulfonique, l'acide éthanesulfonique et l'acide benzènesulfonique, ou leurs solvates pharmaceutiquement acceptables.
PCT/EP2016/076594 2015-11-05 2016-11-03 Sels d'addition de n-[4-(4-{[(1s)-1-(5-méthyl-4-oxo-3-phényl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)éthyl]amino}-7h-pyrrolo[2,3-d]pyrimidin-5-yl)-1h-indol-6-yl]sulfamide WO2017076990A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110305140A (zh) * 2019-07-30 2019-10-08 上海勋和医药科技有限公司 二氢吡咯并嘧啶类选择性jak2抑制剂

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2041763A (en) 1979-02-05 1980-09-17 Chiesi P An inhalor for pulverulent medicinal substances
EP0069715A1 (fr) 1981-07-08 1983-01-12 Aktiebolaget Draco Inhalateur de poudre
EP0166294A2 (fr) 1984-06-18 1986-01-02 Miles Inc. Dispositif d'inhalation d'un médicament
GB2165159A (en) 1984-10-04 1986-04-09 Orion Yhtymae Oy Dosing device
EP0424790A2 (fr) 1989-10-27 1991-05-02 Miat S.P.A. Inhalateur à dosages multiples pour des médicamments sous forme de poudre
WO1992000771A1 (fr) 1990-07-13 1992-01-23 Innovata Biomed Limited Inhalateur
WO1992004068A1 (fr) 1990-08-30 1992-03-19 Boehringer Ingelheim Kg Inhalateur sans gaz propulseur a courant d'air exterieur
WO1992004928A2 (fr) 1990-09-26 1992-04-02 Pharbita B.V. Dispositif d'inhalation pourvu d'un reservoir pour plusieurs doses de produit d'inhalation, dispositif de transport, chambre de turbulence
WO1992009322A1 (fr) 1990-11-29 1992-06-11 Boehringer Ingelheim Kg Dispositif d'inhalation
EP0505321A2 (fr) 1991-03-21 1992-09-23 Ciba-Geigy Ag Inhalateur
DE4239402A1 (de) 1992-11-24 1994-05-26 Bayer Ag Pulverinhalator
EP0674533A1 (fr) 1992-12-18 1995-10-04 Schering Corporation Inhalateur pour medicaments en poudre
WO1997000703A1 (fr) 1995-06-21 1997-01-09 Asta Medica Aktiengesellschaft Cartouche de poudre pharmaceutique avec appareil de dosage integre et inhalateur pour medicaments en poudre
WO2003000325A1 (fr) 2001-06-22 2003-01-03 Sofotec Gmbh & Co. Kg Systeme de desintegration de formulation de poudre et procede pour inhalateurs de poudre seche
WO2006008027A1 (fr) 2004-07-16 2006-01-26 Laboratorios Almirall, S.A. Inhalateur permettant l'administration de produits pharmaceutiques en poudre, et systeme de cartouche de poudre destine a cet inhalateur
WO2014060432A1 (fr) 2012-10-16 2014-04-24 Almirall, S.A. Dérivés de pyrrolotriazinone en tant qu'inhibiteurs des pi3k

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2041763A (en) 1979-02-05 1980-09-17 Chiesi P An inhalor for pulverulent medicinal substances
EP0069715A1 (fr) 1981-07-08 1983-01-12 Aktiebolaget Draco Inhalateur de poudre
EP0166294A2 (fr) 1984-06-18 1986-01-02 Miles Inc. Dispositif d'inhalation d'un médicament
GB2165159A (en) 1984-10-04 1986-04-09 Orion Yhtymae Oy Dosing device
EP0424790A2 (fr) 1989-10-27 1991-05-02 Miat S.P.A. Inhalateur à dosages multiples pour des médicamments sous forme de poudre
WO1992000771A1 (fr) 1990-07-13 1992-01-23 Innovata Biomed Limited Inhalateur
WO1992004068A1 (fr) 1990-08-30 1992-03-19 Boehringer Ingelheim Kg Inhalateur sans gaz propulseur a courant d'air exterieur
WO1992004928A2 (fr) 1990-09-26 1992-04-02 Pharbita B.V. Dispositif d'inhalation pourvu d'un reservoir pour plusieurs doses de produit d'inhalation, dispositif de transport, chambre de turbulence
WO1992009322A1 (fr) 1990-11-29 1992-06-11 Boehringer Ingelheim Kg Dispositif d'inhalation
EP0505321A2 (fr) 1991-03-21 1992-09-23 Ciba-Geigy Ag Inhalateur
DE4239402A1 (de) 1992-11-24 1994-05-26 Bayer Ag Pulverinhalator
EP0674533A1 (fr) 1992-12-18 1995-10-04 Schering Corporation Inhalateur pour medicaments en poudre
WO1997000703A1 (fr) 1995-06-21 1997-01-09 Asta Medica Aktiengesellschaft Cartouche de poudre pharmaceutique avec appareil de dosage integre et inhalateur pour medicaments en poudre
WO2003000325A1 (fr) 2001-06-22 2003-01-03 Sofotec Gmbh & Co. Kg Systeme de desintegration de formulation de poudre et procede pour inhalateurs de poudre seche
WO2006008027A1 (fr) 2004-07-16 2006-01-26 Laboratorios Almirall, S.A. Inhalateur permettant l'administration de produits pharmaceutiques en poudre, et systeme de cartouche de poudre destine a cet inhalateur
WO2014060432A1 (fr) 2012-10-16 2014-04-24 Almirall, S.A. Dérivés de pyrrolotriazinone en tant qu'inhibiteurs des pi3k

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110305140A (zh) * 2019-07-30 2019-10-08 上海勋和医药科技有限公司 二氢吡咯并嘧啶类选择性jak2抑制剂

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