WO2014002059A1 - CRYSTALLINE FORMS OF 1-(2-((1R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1Hpyrazolo[3,4-c]pyridine-3-carboxamide - Google Patents

CRYSTALLINE FORMS OF 1-(2-((1R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1Hpyrazolo[3,4-c]pyridine-3-carboxamide Download PDF

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WO2014002059A1
WO2014002059A1 PCT/IB2013/055301 IB2013055301W WO2014002059A1 WO 2014002059 A1 WO2014002059 A1 WO 2014002059A1 IB 2013055301 W IB2013055301 W IB 2013055301W WO 2014002059 A1 WO2014002059 A1 WO 2014002059A1
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Prior art keywords
crystalline form
hexan
oxoethyl
azabicyclo
carbamoyl
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PCT/IB2013/055301
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French (fr)
Inventor
Christopher Towler
Eva Altmann
Ulrich Hommel
Edwige Liliane Jeanne Lorthiois
Juergen Klaus Maibaum
Nils Ostermann
Jean Quancard
Stefan Andreas Randl
Oliver Simic
Anna Vulpetti
Olivier Rogel
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Novartis Ag
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Publication of WO2014002059A1 publication Critical patent/WO2014002059A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present disclosure generally relates to polymorphic forms of 1-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the present disclosure also generally relates to a pharmaceutical composition comprising the forms, as well of methods of using the form(s) in the treatment of Age-related Macular Degeneration (AMD), and methods for obtaining such forms.
  • AMD Age-related Macular Degeneration
  • the complement system is a crucial component of the innate immunity system and comprises a group of proteins that are normally present in an inactive state. These proteins are organized in three activation pathways: the classical, the lectin, and the alternative pathways (V. M. Holers, In Clinical Immunology: Principles and Practice, ed. R.R. Rich, Mosby Press; 1996, 363-391 ). Molecules from microorganisms, antibodies or cellular components can activate these pathways resulting in the formation of protease complexes known as the C3-convertase and the C5-convertase.
  • the classical pathway is a calcium/magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes.
  • the alternative pathway is a magnesium-dependent cascade which is activated by deposition and activation of C3 on certain susceptible surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).
  • Factor D may be a suitable target for the inhibition of this amplification of the complement pathways because its plasma concentration in humans is very low (about 1 .8 ⁇ g/mL), and it has been shown to be the limiting enzyme for activation of the alternative complement pathway (P.H. Lesavre and H.J. Mijller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; J.E. Volanakis et al., New Eng. J. Med., 1985; 312:395-401 ).
  • Macular degeneration is a clinical term that is used to describe a family of diseases that are characterized by a progressive loss of central vision associated with abnormalities of Bruch's membrane, the choroid, the neural retina and/or the retinal pigment epithelium.
  • the macula lutea In the center of the retina is the macula lutea, which is about 1/3 to 1 ⁇ 2 cm in diameter.
  • the macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density and because of the high ratio of ganlion cells to photoreceptor cells. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all displaced to the side (rather than resting above the photoreceptor cells), thereby allowing light a more direct path to the cones.
  • the choroid Under the retina is the choroid, a part of the uveal tract, and the retinal pigmented epithelium (RPE), which is between the neural retina and the choroid.
  • Age-related macular degeneration is associated with progressive loss of visual acuity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity.
  • Two principal clinical manifestations of AMD have been described as the dry, or atrophic, form and the neovascular, or exudative, form.
  • the dry form is associated with atrophic cell death of the central retina or macula, which is required for fine vision used for activities such as reading, driving or recognizing faces.
  • About 10-20% of these AMD patients progress to the second form of AMD, known as neovascular AMD (also referred to as wet AMD).
  • Neovascular AMD is characterized by the abnormal growth of blood vessels under the macula and vascular leakage, resulting in displacement of the retina, hemorrhage and scarring. This results in a deterioration of sight over a period of weeks to years.
  • Neovascular AMD cases originate from intermediate or advanced dry AMD. The neovascular form accounts for 85% of legal blindness due to AMD. In neovascular AMD, as the abnormal blood vessels leak fluid and blood, scar tissue is formed that destroys the central retina.
  • CNV choroidal neovascularizaton
  • AMD AMD
  • CNF complement factor H
  • the present disclosure provides crystalline forms of 1 -(2-((1 R,3S,5R)-3-(((R)-1- (3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide:
  • Embodiments of these crystalline forms include those characterized herein as Forms A, B, C, D E and F.
  • the names used herein to characterize a specific form e.g. 110 "Form A”, “Form B”, “Form C”, “Form D”, “Form E” and “Form F", should not be
  • FIG. 1 illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form A.
  • FIG. 2 illustrates the differential scanning calorimetry (DSC) of crystalline 1 -(2-
  • FIG. 3. illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3- 125 (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form B.
  • FIG. 4. illustrates the differential scanning calorimetry (DSC) of crystalline 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form 130 B.
  • DSC differential scanning calorimetry
  • FIG. 5 illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form C.
  • FIG. 6. illustrates the differential scanning calorimetry (DSC) of crystalline 1 -(2- 135 ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form C.
  • DSC differential scanning calorimetry
  • FIG. 7 illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- 140 oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form D.
  • FIG. 8. illustrates the differential scanning calorimetry (DSC) of crystalline 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form D.
  • DSC differential scanning calorimetry
  • FIG. 9. illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3-
  • FIG. 10 illustrates the differential scanning calorimetry (DSC) of crystalline 1-(2-
  • FIG. 1 illustrates the x-ray powder diffraction patterns of 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form F.
  • FIG. 12. illustrates the differential scanning calorimetry (DSC) of crystalline 1-(2-
  • the disclosure relates to crystalline forms of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro- 2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, which are described and characterized herein.
  • polymorph refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
  • solvate refers to a crystalline form of a molecule, atom, and/or 170 ions that further comprises molecules of a solvent or solvents incorporated into the
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
  • a solvate with a nonstoichiometric amount of solvent molecules may result from
  • Solvates may occur as dimers or oligomers
  • amorphous refers to a solid form of a molecule, atom, and/or
  • substantially pure when used in reference to a form, means a compound having a purity greater than 90 weight %, including greater than 90 , 91 , 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight %
  • 190 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of 1-(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-
  • the term "substantially pure" with reference to a particular 200 polymorphic form means that the polymorphic form includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1 % by weight of any other physical forms of the compound.
  • a crystalline form of the 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- 205 oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide is provided in substantially pure form.
  • components selected, for example, from the group consisting of excipients, carriers, and one of other active pharmaceutical ingredients active chemical entities of different molecular structure.
  • the crystalline form has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 %
  • composition consisting essentially of the
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form A of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
  • the composition of this embodiment may comprise at least 90 weight % of the crystalline form A of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-
  • the invention is a crystalline form of 1-(2-((1 R,3S,5R)-3-
  • the invention is the crystalline form according to the first embodiment comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
  • the invention is the crystalline form according to the first and second embodiments consisting essentially of Form A.
  • the invention is the crystalline form according to first through the third embodiments wherein said Form A is in substantially pure form.
  • the invention is the crystalline form according to first
  • a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 4.72 ⁇ 0.2°, 5.88 ⁇ 0.2°, 8.40 ⁇ 0.2°, 10.41 ⁇ 0.2°, 1 1 .35 ⁇ 0.2°, 12.76 ⁇ 0.2°, 14.37 ⁇ 0.2°, 14.73 ⁇ 0.2°, 16.39 ⁇ 0.2°, 18.90 ⁇ 0.2°, 19.20 ⁇ 0.2°, 22.99 ⁇ 0.2° and 26.83 ⁇ 0.2°, at a temperature of
  • the invention is the crystalline form according to the fifth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 4.72 ⁇ 0.2°, 5.88 ⁇ 0.2°, 8.40 ⁇ 0.2°, 10.41 ⁇ 0.2°, 1 1.35 ⁇ 0.2°, 12.76 ⁇ 0.2°, 14.37 ⁇ 0.2°, 14.73 ⁇ 0.2°, 16.39 ⁇ 0.2°, 18.90 ⁇ 0.2°, 250 19.20 ⁇ 0.2°, 22.99 ⁇ 0.2° and 26.83 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is a crystalline form of 1 -(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1 .
  • the invention is a crystalline form of 1 -(2-((1 R,3S,5R)-3-
  • the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising 260 the crystalline form according the first through eighth embodiments and a
  • the invention is the pharmaceutical composition according to the ninth embodiment wherein said crystalline form is Form A.
  • the invention is the pharmaceutical composition 265 according to the tenth embodiment wherein said Form A is in substantially pure form.
  • the invention is a combination, in particular a
  • composition comprising a therapeutically effective amount of the crystalline from according to any one of the first through eighth embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition
  • the invention is the pharmaceutical composition according to the thirteenth embodiment wherein said Form A is in substantially pure form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-
  • the invention is the method according to the fifteenth embodiment wherein said crystalline form is Form A.
  • the invention is the method according to the
  • the invention is the method according to the fifteenth embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 weight % of the crystalline form according to the second through eighth embodiments
  • the invention is a process of making Form A of 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 1.
  • composition consisting essentially of the
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form B of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
  • the composition of this embodiment may comprise at least 90 weight % of the crystalline form B of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-
  • the invention is the crystalline form according to the
  • first embodiment comprising 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide Form B.
  • the invention is the crystalline form according to the first and twenty first embodiments consisting essentially of Form B.
  • the invention is the crystalline form according to claims first and twenty first through twenty second embodiments wherein said Form B is in substantially pure form.
  • the invention is the crystalline form according to the first and twenty first through twenty third embodiments characterized by a x-ray
  • 315 powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 7.37 ⁇ 0.2°, 7.84 ⁇ 0.2°, 9.18 ⁇ 0.2°, 1 1 .06 ⁇ 0.2°, 12.21 ⁇ 0.2°, 13.04 ⁇ 0.2°, 14.59 ⁇ 0.2°, 15.41 ⁇ 0.2°, 16.13 ⁇ 0.2°, 17.07 ⁇ 0.2°, 18.01 ⁇ 0.2°, 18.83 ⁇ 0.2°, 19.58 ⁇ 0.2°, 19.93 ⁇ 0.2°, 20.12 ⁇ 0.2°, 20.64 ⁇ 0.2°, 20.96 ⁇ 0.2°, 21 .36 ⁇ 0.2°, 22.07 ⁇ 0.2°, 22.60 ⁇ 0.2°, 22.99 ⁇ 0.2°, 24.46 ⁇ 0.2°, 24.83 ⁇ 0.2°, 25.25 ⁇ 0.2°, 25.85 ⁇ 0.2°, 26.61 ⁇ 0.2°, 27.07 ⁇ 0.2°, 320 27.54 ⁇ 0.2°, 28.33 ⁇ 0.2° and 29.53 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is the crystalline form according to the twenty fourth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 20 values selected from the group consisting of 7.37 ⁇ 0.2°, 7.84 ⁇ 0.2°, 9.18 ⁇ 0.2°, 1 1 .06 ⁇ 0.2°, 12.21 ⁇ 0.2°, 13.04 ⁇ 0.2°, 14.59 ⁇ 0.2°, 15.41 ⁇ 0.2°, 325 16.13 ⁇ 0.2°, 17.07 ⁇ 0.2°, 18.01 ⁇ 0.2°, 18.83 ⁇ 0.2°, 19.58 ⁇ 0.2°, 19.93 ⁇ 0.2°, 20.12 ⁇ 0.2°, 20.64 ⁇ 0.2°, 20.96 ⁇ 0.2°, 21 .36 ⁇ 0.2°, 22.07 ⁇ 0.2°, 22.60 ⁇ 0.2°, 22.99 ⁇ 0.2°, 24.46 ⁇ 0.2°, 24.83 ⁇ 0.2°, 25.25 ⁇ 0.2°, 25.85 ⁇ 0.2°, 26.61 ⁇ 0.2°, 27.07 ⁇ 0.2°, 27.54 ⁇ 0.2°, 28.33 ⁇ 0.2° and 29.53 ⁇ 0.2°,
  • the invention is a crystalline form of 1-(2- 330 ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 3.
  • the invention a crystalline form of 1 -(2- 335 ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 4.
  • DSC differential scanning calorimetry
  • the invention is a pharmaceutical composition 340 comprising the crystalline form according to first and twenty first through the twenty seventh embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical composition according to the twenty eighth embodiment wherein said crystalline form is Form B.
  • the invention is the pharmaceutical composition 345 according to the twenty ninth embodiment wherein said Form B is in substantially pure form.
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of first and twenty first through the twenty seventh 350 embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition according to the thirty first embodiment wherein said crystalline form is Form B.
  • the invention is the pharmaceutical composition according to the thirty second embodiment wherein said Form B is in substantially pure 355 form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1 -(2-((1 R,3S,5R)-3-
  • the invention is the method according to the thirty fourth embodiment wherein said crystalline form is Form B.
  • the invention is the method according to the thirty fifth embodiment wherein said Form B is in substantially pure form.
  • the invention is the method according to the thirty fourth embodiment wherein the subject is a human.
  • the invention is a composition comprising at least
  • the invention is a process of making Form B of 1-(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide
  • a composition consisting essentially of the crystalline form C of the 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
  • the composition of this embodiment may
  • 380 comprise at least 90 weight % of the crystalline form C of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1-(2-((1 R,3S,5R)-3-(((R)- 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide in the composition.
  • the invention is the crystalline form according to the first embodiment comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide Form C.
  • the invention is the crystalline form according to
  • the invention is the crystalline form according to first and fortieth through forty first embodiments wherein said Form C is in substantially pure form. In a forty third embodiment, the invention is the crystalline form according to the
  • diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 6.93 ⁇ 0.2°, 8.83 ⁇ 0.2°, 10.58 ⁇ 0.2°, 1 1 .56 ⁇ 0.2°, 12.98 ⁇ 0.2°, 13.56 ⁇ 0.2°, 14.04 ⁇ 0.2°, 14.60 ⁇ 0.2°, 14.85 ⁇ 0.2°, 16.65 ⁇ 0.2°, 17.41 ⁇ 0.2°, 17.77 ⁇ 0.2°, 18.46 ⁇ 0.2°, 19.54 ⁇ 0.2°, 21.38 ⁇ 0.2°, 22.03 ⁇ 0.2°, 22.75 ⁇ 0.2°, 24.53 ⁇ 0.2°, 25.1 1 ⁇ 0.2°, 25.77 ⁇ 0.2°, 26.62 ⁇ 0.2°,
  • the invention is the crystalline form according to claim 43 further characterized by a x-ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 6.93 ⁇ 0.2°, 8.83 ⁇ 0.2°, 10.58 ⁇ 0.2°, 1 1.56 ⁇ 0.2°, 12.98 ⁇ 0.2°, 13.56 ⁇ 0.2°, 14.04 ⁇ 0.2°, 14.60 ⁇ 0.2°, 14.85 ⁇ 0.2°, 16.65 ⁇ 0.2°,
  • the invention is a crystalline form of 1 -(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-
  • the invention is a crystalline form of 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide
  • DSC differential scanning calorimetry
  • the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form according to the first and fortieth through forty sixth embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical composition according to the forty seventh embodiment wherein said crystalline form is Form C.
  • the invention is the pharmaceutical composition according to the forty eighth embodiment wherein said Form C is in substantially pure form.
  • the invention is a combination, in particular a
  • composition comprising a therapeutically effective amount of the crystalline from according to any one of the first and fortieth through forty sixth embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition
  • the invention is the pharmaceutical composition according to the fifty first embodiment wherein said Form C is in substantially pure form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by 435 activation of the complement alternative pathway, comprising administering to the
  • the invention is the method according to the fifty third embodiment wherein said crystalline form is Form C.
  • the invention is the method according to the fifty fourth embodiment wherein said Form C is in substantially pure form.
  • the invention is the method according to the fifty third 445 embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 weight % of the crystalline form according to the first and fortieth through forty sixth embodiments, based on the weight of the composition.
  • the invention is a process of making Form C of 1 -(2- 450 ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 3.
  • a composition consisting essentially of the crystalline form D of the 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- 455 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form D of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1-(2-((1 R,3S,5R)-3-(((R)- 460 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide in the composition.
  • the invention is the crystalline form according to the first embodiment comprising 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- 465 pyrazolo[3,4-c]pyridine-3-carboxamide Form D.
  • the invention is the crystalline form according to first and fifty ninth embodiments consisting essentially of Form D.
  • the invention is the crystalline form according to the first and fifty ninth through sixtieth embodiments wherein said Form D is in substantially 470 pure form.
  • the invention is the crystalline form according to the first and fifty ninth through sixty first embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 6.03 ⁇ 0.2°, 7.23 ⁇ 0.2°, 7.79 ⁇ 0.2°, 8.19 ⁇ 0.2°, 9.26 ⁇ 0.2°, 10.85 ⁇ 0.2°, 1 1 .63 ⁇ 0.2°, 475 12.62 ⁇ 0.2°, 12.95 ⁇ 0.2°, 13.66 ⁇ 0.2°, 14.17 ⁇ 0.2°, 14.71 ⁇ 0.2°, 15.31 ⁇ 0.2°, 16.14 ⁇ 0.2°, 17.15 ⁇ 0.2°, 17.55 ⁇ 0.2°, 18.33 ⁇ 0.2°, 19.16 ⁇ 0.2°, 19.69 ⁇ 0.2°, 20.27 ⁇ 0.2°, 21.82 ⁇ 0.2°, 22.45 ⁇ 0.2°, 23.43 ⁇ 0.2°, 25.05 ⁇ 0.2°, 27.48 ⁇ 0.2°, 28.35 ⁇ 0.2°, 28.76 ⁇ 0.2° and 29.56 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is the crystalline form according to the 480 sixty second embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 6.03 ⁇ 0.2°, 7.23 ⁇ 0.2°, 7.79 ⁇ 0.2°, 8.19 ⁇ 0.2°, 9.26 ⁇ 0.2°, 10.85 ⁇ 0.2°, 1 1.63 ⁇ 0.2°, 12.62 ⁇ 0.2°, 12.95 ⁇ 0.2°, 13.66 ⁇ 0.2°, 14.17 ⁇ 0.2°, 14.71 ⁇ 0.2°, 15.31 ⁇ 0.2°, 16.14 ⁇ 0.2°, 17.15 ⁇ 0.2°, 17.55 ⁇ 0.2°, 18.33 ⁇ 0.2°, 19.16 ⁇ 0.2°, 19.69 ⁇ 0.2°, 20.27 ⁇ 0.2°, 21.82 ⁇ 0.2°, 22.45 ⁇ 0.2°, 485 23.43 ⁇ 0.2°, 25.05 ⁇ 0.2°, 27.48 ⁇ 0.2°, 28.35 ⁇ 0.2°, 28.76 ⁇ 0.2° and 29.56 ⁇ 0.2°, at a
  • the invention is a crystalline form of 1-(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide 490 having a X-ray diffraction spectrum substantially the same as the X-ray powder
  • the invention is a crystalline form of 1-(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning 495 calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 8.
  • DSC differential scanning 495 calorimetry
  • the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form according to the first and fifty ninth through sixty fifth embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical composition 500 according to the sixty sixth embodiment wherein said crystalline form is Form D.
  • the invention is the pharmaceutical composition according to the sixty seventh embodiment wherein said Form D is in substantially pure form.
  • the invention is a combination, in particular a 505 pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first and fifty ninth through sixty fifth embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition according to the sixty ninth embodiment wherein said crystalline form is Form D.
  • the invention is the pharmaceutical composition according to the seventieth embodiment wherein said Form D is in substantially pure form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by 515 activation of the complement alternative pathway, comprising administering to the
  • the invention is the method according to the
  • the invention is the method according to the seventy third embodiment wherein said Form D is in substantially pure form.
  • the invention is the method according to the 525 seventy second embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 weight % of the crystalline form according to the first and fifty ninth through sixty fifth embodiments based on the weight of the composition.
  • the invention is a process of making Form D of 530 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 4.
  • a composition consisting essentially of the crystalline form E of the 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- 535 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form E of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1-(2-((1 R,3S,5R)-3-(((R)- 540 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide in the composition.
  • the invention is the crystalline form according to the first embodiment comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- 545 pyrazolo[3,4-c]pyridine-3-carboxamide Form E.
  • the invention is the crystalline form according to the first and seventy eighth embodiments consisting essentially of Form E.
  • the invention is the crystalline form according to the first and seventy eighth through seventy ninth embodiments wherein said Form E is in 550 substantially pure form.
  • the invention is the crystalline form according to the first and seventy eighth through eightieth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 4.76 ⁇ 0.2°, 7.67 ⁇ 0.2°, 8.56 ⁇ 0.2°, 10.45 ⁇ 0.2°, 13.24 ⁇ 0.2°, 13.89 ⁇ 0.2°, 14.63 ⁇ 0.2°, 555 14.96 ⁇ 0.2°, 15.53 ⁇ 0.2°, 16.13 ⁇ 0.2°, 16.51 ⁇ 0.2°, 17.63 ⁇ 0.2°, 19.06 ⁇ 0.2°, 21.95 ⁇ 0.2°, 22.43 ⁇ 0.2°, 25.97 ⁇ 0.2°, 26.95 ⁇ 0.2° and 27.80 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is the crystalline form according to the eighty first embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 4.76 ⁇ 0.2°, 560 7.67 ⁇ 0.2°, 8.56 ⁇ 0.2°, 10.45 ⁇ 0.2°, 13.24 ⁇ 0.2°, 13.89 ⁇ 0.2°, 14.63 ⁇ 0.2°, 14.96 ⁇ 0.2°,
  • the invention is a crystalline form of 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- 565 azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide
  • the invention is a crystalline form of 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- 570 azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide
  • DSC differential scanning calorimetry
  • the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form according to the first and seventy eighth through eighty 575 fourth embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical composition according to the eighty fifth embodiment wherein said crystalline form is Form E.
  • the invention is the pharmaceutical composition according to the eighty sixth embodiment wherein said Form E is in 580 substantially pure form.
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first and seventy eighth through eighty fourth embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition according to the eighty eighth embodiment wherein said crystalline form is Form E.
  • the invention is the pharmaceutical composition according to the eighty ninth embodiment wherein said Form E is in substantially pure form.
  • the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-
  • the invention is the method according to the ninety first embodiment wherein said crystalline form is Form E.
  • the invention is the method according to the ninety
  • the invention is the method according to ninety first embodiment wherein the subject is a human.
  • the invention is acomposition comprising at least 90 weight % of the crystalline form according to the first and seventy eighth through eighty
  • the invention is a process of making Form E of 1 - (2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 5.
  • composition consisting essentially of the
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form F of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
  • the composition of this embodiment may comprise at least 90 weight % of the crystalline form F of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-
  • the invention is the crystalline form according to the first embodiment comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide Form F.
  • the invention is the crystalline form according to the first and ninety seventh embodiments consisting essentially of Form F.
  • the invention is the crystalline form according to the first and ninety seventh through ninety eighth embodiments wherein said Form F is in substantially pure form.
  • the invention is the crystalline form according to the first and ninety seventh through ninety ninth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2 ⁇ values selected from the group consisting of 6.91 ⁇ 0.2°, 7.99 ⁇ 0.2°, 8.85 ⁇ 0.2°, 9.64 ⁇ 0.2°, 10.58 ⁇ 0.2°, 1 1.80 ⁇ 0.2°, 13.60 ⁇ 0.2°, 14.74 ⁇ 0.2°, 15.15 ⁇ 0.2°, 16.77 ⁇ 0.2°, 17.46 ⁇ 0.2°, 18.07 ⁇ 0.2°, 18.64 ⁇ 0.2°, 19.07 ⁇ 0.2°, 20.45 ⁇ 0.2°, 21 .52 ⁇ 0.2°, 21 .89 ⁇ 0.2°, 23.45 ⁇ 0.2°, 26.10 ⁇ 0.2°, 26.76 ⁇ 0.2°, 27.62 ⁇ 0.2° and 27.89 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is the crystalline form according to hundredth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2 ⁇ values selected from the group consisting of 6.91 ⁇ 0.2°, 7.99 ⁇ 0.2°, 8.85 ⁇ 0.2°, 9.64 ⁇ 0.2°, 10.58 ⁇ 0.2°, 1 1.80 ⁇ 0.2°, 13.60 ⁇ 0.2°, 14.74 ⁇ 0.2°, 15.15 ⁇ 0.2°, 16.77 ⁇ 0.2°, 17.46 ⁇ 0.2°, 18.07 ⁇ 0.2°, 18.64 ⁇ 0.2°, 19.07 ⁇ 0.2°, 20.45 ⁇ 0.2°, 21.52 ⁇ 0.2°, 21.89 ⁇ 0.2°, 23.45 ⁇ 0.2°, 26.10 ⁇ 0.2°, 26.76 ⁇ 0.2°, 27.62 ⁇ 0.2° and 27.89 ⁇ 0.2°, at a temperature of about 22°C.
  • the invention is a crystalline form of 1-(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1 1 .
  • the invention is a crystalline form of 1-(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 12.
  • DSC differential scanning calorimetry
  • the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form according to the first and ninety seventh through the hundred third embodiments and a pharmaceutically acceptable carrier or diluent.
  • the invention is the pharmaceutical composition according to the hundred fourth embodiment wherein said crystalline form is Form F.
  • the invention is the pharmaceutical composition according to the hundred fifth embodiment wherein said Form F is in substantially pure form.
  • the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first and ninety seventh through the hundred third embodiments and a second therapeutically active agent.
  • the invention is the pharmaceutical composition 665 according to the hundred seventh embodiment wherein said crystalline form is Form F.
  • the invention is the pharmaceutical composition according to the hundred eighth embodiment wherein said Form F is in substantially pure form.
  • the invention is a method of treating a disorder 670 or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to the first and ninety 675 seventh through the hundred third embodiments.
  • the invention is the method according to the hundred tenth embodiment wherein said crystalline form is Form F.
  • the invention is the method according to the hundred eleventh embodiment wherein said Form F is in substantially pure form.
  • the invention is the method according to the hundred tenth embodiment wherein the subject is a human.
  • the invention is a composition comprising at least 90 weight % of the crystalline form according to the first and ninety seventh through the hundred third embodiments based on the weight of the composition.
  • the invention is a process of making Form A of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 6.
  • reaction impurities and/or processing impurities may be 690 determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy.
  • the present invention provides a crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
  • inter-apparatus variability typically as much as 0.2°.
  • relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.
  • Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of
  • crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture.
  • High throughput crystallization techniques may be employed to prepare crystalline forms including
  • Crystals of drugs including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2 nd Edition, SSCI, West Lafayette, Indiana (1999).
  • 720 solvents is typically dependent upon one or more factors, such as solubility of the
  • solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals.
  • antisolvent is a solvent in which the compound has low solubility.
  • a compound is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution.
  • a suitable solvent to afford a slurry, which may be heated to promote dissolution.
  • slurry means a saturated solution of the compound, which may also contain an additional amount of the compound to afford a heterogeneous mixture of the compound
  • Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an
  • a cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form.
  • a suitable solvent such as cold recrystallization solvent
  • the resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the
  • the product may be comilled or passed through a mesh screen to delump the product, if necessary.
  • Crystalline forms may be prepared directly from the reaction medium of the final process for preparing 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
  • pyrazolo[3,4-c]pyridine-3-carboxamide This may be achieved, for example, by employing in the final process step a solvent or a mixture of solvents from which 1-(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide may be crystallized. Alternatively, crystalline forms may be obtained by distillation or solvent addition techniques. Suitable
  • solvents for this purpose include, for example, the aforementioned nonpolar solvents and polar solvents, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.
  • the presence of more than one polymorph in a sample may be determined by techniques such as x-ray powder diffraction (PXRD) or solid state nuclear magnetic 765 resonance spectroscopy.
  • PXRD x-ray powder diffraction
  • the simulated PXRD may be calculated from single crystal x-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, 770 UCRL-7196 (April 1963) or TOPAS program (Total Pattern Analysis Solution, available through Brucker AXS Inc.).
  • intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken
  • a measurement error of diffraction angle for a conventional X- ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to
  • the DSC instrument used to test the crystalline forms was a TA Instrument® Differential Scanning Calorimetry Model 2910, TA Instruments® Modulated Differential Scanning Calorimetry Model 2920, or TA Instruments® Modulated Differential Scanning Calorimetry Model Q1000.
  • the DSC cell/sample chamber was purged with 100 ml/min of
  • the instrument was calibrated with high purity indium. The accuracy of the measured sample temperature with this method is within about ⁇ 1 °C, and the heat of fusion can be measured within a relative error of about ⁇ 5%.
  • the sample was placed into an open aluminum DSC pan and measured against an empty reference pan. About 2-6 mg of sample powder was placed into the bottom of the pan and lightly
  • the instrument was programmed to heat at 10°C. per minute in the temperature range between 25 and 300°C.
  • the heat flow which was normalized by a sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram ("W/g"). 805 The plot was made with the endothermic peaks pointing down. The endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.
  • the TGA instruments used to test the crystalline forms was a TA
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and ophthalmic administration, etc.
  • the pharmaceutical compositions of the present invention can be formulated for particular routes of administration such as oral administration, parenteral administration, and ophthalmic administration, etc.
  • 820 can be made up in a solid form (including without limitation capsules, tablets, pills,
  • compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert
  • preservatives preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose 830 and/or glycine;
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
  • binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or
  • disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • Tablets may be either film coated or enteric coated according to methods known 840 in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the
  • agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide
  • Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, corn starch, or alginic acid
  • binding agents for example, starch, gelatin or acacia
  • lubricating agents for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium
  • 860 phosphate or kaolin or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving,
  • compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier.
  • Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally 875 with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g.,
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • the present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous
  • compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
  • the invention further provides pharmaceutical compositions and dosage forms
  • antioxidants include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
  • the present invention provides methods of treating a disease or disorder associated with increased complement activity by administering to a subject in need thereof an effective amount of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-
  • 945 complement activation is induced by antibody-antigen interactions, by a component of an autoimmune disease, or by ischemic damage.
  • the present invention provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-31 -(2-((1 R,3S,5R)-3-
  • AMD age-related macular degeneration
  • patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration related disorder are suitable for administration with a compound of the invention.
  • the methods of treating or preventing AMD include, but are not limited to,
  • AMD advanced forms of AMD
  • AMD advanced forms of AMD
  • macular edema from AMD or other conditions (such as diabetic retinopathy, uveitis, or post surgical or non-surgical trauma)
  • AMD macular edema
  • AMD diabetic retinopathy, uveitis, or post surgical or non-surgical trauma
  • the present invention further provides methods of treating a complement related disease or disorder by administering to a subject in need thereof an effective amount of the compound(s) of the invention, wherein said disease or disorder is selected from uveitis, adult macuar degeneration, diabetic
  • retinopathy 975 retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, and retinal vein occlusion.
  • the present invention provides methods of treating a
  • complement related disease or disorder by administering to a subject in need thereof an effective amount of the compounds of the invention.
  • known complement related diseases or disorders include: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications,
  • lung disease and disorders such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen
  • sulfide 1000 sulfide, nitrogen dioxide, ammonia, and hydrochloric acid
  • smoke injury thermal injury (e.g., burn, freeze), asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, uveitis (including Behcet's disease and other sub-types of uveitis), antiphospholipid syndrome.
  • the present invention provides methods of treating a complement related disease or disorder by administering to a subject in need thereof an effective amount of the compounds of the invention, wherein said disease or disorder is asthma, arthritis (e.g., rheumatoid arthritis), autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injuries, Barraquer-Simons
  • sclerosis transplantation, diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions, atypicaly hemolytic uremic syndrome (aHUS), glomerulonephritis (including membrane proliferative glomerulonephritis), blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and
  • the present invention provides methods of treating glomerulonephritis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the present invention.
  • glomerulonephritis include, but not limited to, proteinuria; reduced glomerular filtration
  • the present invention provides methods of treating paroxysmal nocturnal hemoglobinuria (PNH) by
  • the present invention provides methods of reducing the dysfunction of the immune and/or hemostatic systems associated with extracorporeal
  • composition comprising an compound of the present invention.
  • 1-(2-((1 R,3S,5R)-3-(((R)- 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide can be used in any procedure which involves circulating the patient's blood from a blood vessel of the patient, through a conduit, and
  • the conduit having a luminal surface comprising a material capable of causing at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte adhesion.
  • Such procedures include, but are not limited to, all forms of ECC, as well as procedures involving the introduction of an artificial or foreign organ, tissue, or vessel into the blood circuit of a patient. More
  • such procedures include, but are not limited to, transplantation procedures including kidney, liver, lung or heart transplant procedures and islet cell transplant procedures.
  • the compounds of the invention are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including
  • the compounds of the invention may be used in blood ampules, diagnostic kits and other equipment used in the collection and sampling of blood.
  • the use of the compounds of the invention in such diagnostic kits may inhibit the ex vivo activation of the complement pathway associated with blood sampling.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1 -1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1 -500 mg or about 1 -250 mg or about 1 -150 mg or about 0.5-100 mg, or about 1 -50 mg of active ingredients.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests 1060 using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 "3 molar and 10 "9 1065 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1 -500 mg/kg, or between about 1-100 mg/kg.
  • the activity of a compound according to the present invention can be assessed by the following in vitro & in vivo methods.
  • the compound of the present invention may be administered either
  • the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
  • the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease or condition mediated by alternative complement pathway.
  • Products provided as a combined preparation include a composition comprising 1 -(2-
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide and another therapeutic agent(s).
  • the pharmaceutical composition may comprise
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains 1 -(2-((1 R,3S,5R)-3-(((R)-1- (3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
  • the kit comprises means for
  • compositions such as a container, divided bottle, or divided foil packet.
  • a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage forms, for example, oral and parenteral, for administering the separate compositions at different
  • the kit of the invention typically comprises directions for administration.
  • the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other
  • 1 105 therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient
  • the invention provides the use of 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide for treating a disease or condition mediated by the complement alternative pathway, wherein the medicament is prepared for
  • the invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the
  • the invention also provides 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide for use in a method of treating a disease or condition mediated by the complement alternative pathway, wherein 1 1 -(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-
  • 1 125 oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor D, wherein the other therapeutic agent is prepared for
  • the invention also provides 1 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor D, wherein 1 -
  • the invention also provides the use of 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide for treating a disease or condition mediated by
  • the invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the complement alternative pathway and/or Factor D wherein the patient has previously (e.g. within 24 hours) been treated with 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-
  • compositions can be administered alone or in combination with other molecules known to have a beneficial effect on retinal attachment or damaged retinal tissue, including molecules capable of tissue repair and regeneration and/or
  • anti-VEGF agents such as an antibody or FAB against VEGF, e.g., Lucentis or Avastin
  • VEGF agents such as an antibody or FAB against VEGF, e.g., Lucentis or Avastin
  • basic fibroblast growth factor (bFGF) basic fibroblast growth factor (bFGF)
  • ciliary neurotrophic factor (CNTF) ciliary neurotrophic factor (CNTF), axokine (a mutein of CNTF), leukemia inhibitory factor (LI F), neutrotrophin 3 (NT-3), neurotrophin-4 (NT-4), nerve growth factor (NGF), insulin-like growth factor I I, prostaglandin E2, 30 kD survival factor, taurine, and
  • agents for combination treatment with the compounds of the invention include agents known in the art that are able to modulate the activities of complement components.
  • a combination therapy regimen may be additive, or it may produce synergistic results (e.g., reductions in complement pathway activity more than expected for the combined use of the two agents).
  • the present invention provide a combination therapy for preventing and/or treating AMD or another complement related ocular disease as described above with a compound of the invention and an anti- 1170 angiogenic, such as anti-VEGF agent (including Lucentis and Avastin) or photodynamic therapy (such as verteporfin).
  • the present invention provide a combination therapy for preventing and/or treating autoimmune disease as described above with a compound of the invention and a B-Cell or T-Cell modulating agent (for example cyclosporine or
  • for multiple sclerosis therapy may include the combination of a compound of the invention and a second MS agent selected from fingolimod, cladribine, tysarbi, laquinimod, rebif, avonex and the like.
  • the invention provides a method of modulating activity of the
  • the invention further provides methods of modulating the activity of the complement alternative pathway in a subject by
  • 1185 modulating the activity of Factor D wherein the method comprises administering to the subject a therapeutically effective amount of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
  • the invention provides 1-(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-
  • the invention provides the use of 1 -(2-((1 R,3S,5R)-3-(((R)-1 - (3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, for the treatment of a disorder or disease in a
  • the invention provides the use of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide, for the treatment of a disorder or disease mediated by activation of the complement alternative pathway.
  • the invention provides the use of 1 -(2-((1 R,3S,5R)-3-(((R)-1 -
  • the invention provides the use of 1 1-(2-((1 R,3S,5R)-3-(((R)- 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for the treatment of a disorder or disease in a
  • the invention provides uses of the compounds provided herein in the treatment of a disease or disorder characterized by over activiation of the complement alternative pathway or the C3 amplification loop of the alternative pathway.
  • the use is in the treatment of a disease or disorder is selected from retinal diseases (such as age-
  • the present invention provides use of the compounds of the invention for treating a disease or disorder associated with increased complement activity by administering to a subject in need thereof an effective amount of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
  • uses are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway.
  • uses of treating or preventing compelment mediated diseases are provided in which the complement activation is induced by antibody-antigen interactions, by a component of an autoimmune disease, or
  • the present invention provides use of the compounds of the invention for treating or preventing age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration related disorder are suitable for
  • AMD 1230 administration with a compound of the invention.
  • the use in treating or preventing AMD include, but are not limited to, uses in treating or preventing one or more symptoms or aspects of AMD selected from formation of ocular drusen, inflammation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including loss of visual acuity or visual field), neovascularization (including CNV), retinal detachment, photoreceptor
  • RPE degeneration RPE degeneration
  • retinal degeneration chorioretinal degeneration
  • cone degeneration retinal dysfunction
  • retinal damage in response to light exposure damage of the Bruch's membrane, and/ or loss of RPE function.
  • ⁇ 1240 be used, inter alia, to prevent the onset of AMD, to prevent the progression of early AMD to advanced forms of AMD including neovascular AMD or geographic atrophy, to slow and/or prevent progression of geographic atrophy, to treat or prevent macular edema from AMD or other conditions (such as diabetic retinopathy, uveitis, or post surgical or non-surgical trauma), to prevent or reduce the loss of vision from AMD, and to improve
  • the present invention further provides methods of treating a complement related disease or disorder by administering to a subject in need thereof an effective amount of the compound(s) of the invention, wherein said
  • disease or disorder is selected from uveitis, adult macuar degeneration, diabetic
  • retinopathy retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, and retinal vein occlusion.
  • the present invention provides uses for treating a
  • complement related disease or disorder examples include: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft
  • inflammatory disorders inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post- pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis,
  • nitrogen dioxide, ammonia, and hydrochloric acid 1275 nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze), asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, uveitis (including Behcet's disease and other sub-types of uveitis), antiphospholipid syndrome.
  • thermal injury e.g., burn, freeze
  • asthma e.g., allergy, bronchoconstriction
  • hypersensitivity pneumonitis e.g., parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation
  • uveitis including Behcet's disease and other sub-types of uveitis
  • the present invention provides use of 1 -(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 ]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for treating a complement related disease or disorder, wherein said disease or disorder is asthma, arthritis (e.g., rheumatoid arthritis), autoimmune heart disease, multiple sclerosis, inflammatory bowel syndrome, and others.
  • glomerulonephritis including membrane proliferative glomerulonephritis), blistering
  • cutaneous diseases including bullous pemphigoid, pemphigus, and epidermolysis
  • the present invention provides use of 1 -(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for treating glomerulonephritis.
  • Symptoms of glomerulonephritis include, but not limited to, proteinuria; reduced
  • GFR glomerular filtration rate
  • serum electrolyte changes including azotemia (uremia, excessive blood urea nitrogen-BUN) and salt retention, leading to water retention resulting in hypertension and edema; hematuria and abnormal urinary sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and lipiduria.
  • azotemia uremia, excessive blood urea nitrogen-BUN
  • salt retention leading to water retention resulting in hypertension and edema
  • hematuria and abnormal urinary sediments including red cell casts
  • hypoalbuminemia hyperlipidemia
  • lipiduria glomerular filtration rate
  • the present invention provides methods of treating paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition comprising an compound of the present invention with or without concomitent administration of a complement C5 inhibitor or C5 convertase inhibitor such as Soliris.
  • PNH paroxysmal nocturnal hemoglobinuria
  • the present invention provides use 1 -(2-((1 R,3S,5R)-3-
  • 1310 azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide can be used in any procedure which involves circulating the patient's blood from a blood vessel of the patient, through a conduit, and back to a blood vessel of the patient, the conduit having a luminal surface comprising a material capable of causing at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte
  • Such procedures include, but are not limited to, all forms of ECC, as well as procedures involving the introduction of an artificial or foreign organ, tissue, or vessel into the blood circuit of a patient. More particularly, such procedures include, but are not limited to, transplantation procedures including kidney, liver, lung or heart transplant procedures and islet cell transplant procedures.
  • This form was crystalline by XRPD and the DSC trace is characterized by a broad endothermic event starting at ambient temperature followed by an endothermic event at ⁇ 125°C immediately followed by an exothermic event at ⁇ 140°C and a higher temperature endotherm at
  • the DSC for Form E is shown in Figure 10.
  • Differential scanning calorimetry was conducted for each crystalline form using a TA InstrumentsTM model Q1000.
  • the DSC cell/sample chamber was purged with 100 ml/min of ultra-high purity nitrogen gas.
  • the instrument was calibrated with high purity indium.
  • the heating rate was 10 C per minute in the temperature range
  • the TGA instruments used to test the crystalline forms was a TA

Abstract

Crystalline forms of 11-(2-((1R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H- pyrazolo[3,4-c]pyridine-3-carboxamide. 1-(2-((1R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H- pyrazolo[3,4-c]pyridine-3-carboxamide is useful in treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway.

Description

CRYSTALLINE FORMS OF 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide
FIELD OF INDUSTRIAL APPLICABILITY
The present disclosure generally relates to polymorphic forms of 1-(2-
((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide. The present disclosure also generally relates to a pharmaceutical composition comprising the forms, as well of methods of using the form(s) in the treatment of Age-related Macular Degeneration (AMD), and methods for obtaining such forms.
BACKGROUND OF THE DISCLOSURE
The complement system is a crucial component of the innate immunity system and comprises a group of proteins that are normally present in an inactive state. These proteins are organized in three activation pathways: the classical, the lectin, and the alternative pathways (V. M. Holers, In Clinical Immunology: Principles and Practice, ed. R.R. Rich, Mosby Press; 1996, 363-391 ). Molecules from microorganisms, antibodies or cellular components can activate these pathways resulting in the formation of protease complexes known as the C3-convertase and the C5-convertase. The classical pathway is a calcium/magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes. It can also be activated in an antibody- independent manner by the binding of C-reactive protein complexed to ligand and by many pathogens including gram-negative bacteria. The alternative pathway is a magnesium-dependent cascade which is activated by deposition and activation of C3 on certain susceptible surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).
Factor D may be a suitable target for the inhibition of this amplification of the complement pathways because its plasma concentration in humans is very low (about 1 .8 μg/mL), and it has been shown to be the limiting enzyme for activation of the alternative complement pathway (P.H. Lesavre and H.J. Mijller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; J.E. Volanakis et al., New Eng. J. Med., 1985; 312:395-401 ).
Macular degeneration is a clinical term that is used to describe a family of diseases that are characterized by a progressive loss of central vision associated with abnormalities of Bruch's membrane, the choroid, the neural retina and/or the retinal pigment epithelium. In the center of the retina is the macula lutea, which is about 1/3 to ½ cm in diameter. The macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density and because of the high ratio of ganlion cells to photoreceptor cells. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all displaced to the side (rather than resting above the photoreceptor cells), thereby allowing light a more direct path to the cones. Under the retina is the choroid, a part of the uveal tract, and the retinal pigmented epithelium (RPE), which is between the neural retina and the choroid. The choroidal blood vessels provide nutrition to the retina and its visual cells.
Age-related macular degeneration (AMD), the most prevalent form of macular degeneration, is associated with progressive loss of visual acuity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity. Two principal clinical manifestations of AMD have been described as the dry, or atrophic, form and the neovascular, or exudative, form. The dry form is associated with atrophic cell death of the central retina or macula, which is required for fine vision used for activities such as reading, driving or recognizing faces. About 10-20% of these AMD patients progress to the second form of AMD, known as neovascular AMD (also referred to as wet AMD).
Neovascular AMD is characterized by the abnormal growth of blood vessels under the macula and vascular leakage, resulting in displacement of the retina, hemorrhage and scarring. This results in a deterioration of sight over a period of weeks to years. Neovascular AMD cases originate from intermediate or advanced dry AMD. The neovascular form accounts for 85% of legal blindness due to AMD. In neovascular AMD, as the abnormal blood vessels leak fluid and blood, scar tissue is formed that destroys the central retina.
The new blood vessels in neovascular AMD are usually derived from the choroid and are referred to as choroidal neovascularizaton (CNV). The pathogenesis of new choroidal vessels is poorly understood, but such factors as inflammation, ischemia, and local production of angiogenic factors are thought to be important. A published study suggests that CNV is caused by complement activation in a mouse laser model (Bora P.S., J. Immunol. 2005; 174; 491 -497).
Human genetic evidence implicates the involvement of the complement system, particularly the alternative pathway, in the pathogenesis of Age-related Macular
Degeneration (AMD). Significant associations have been found between AMD and polymorphisms in complement factor H (CFH) (Edwards AO, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005 Apr
15;308(5720):421 -4; Hageman GS, et al Acommon haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005 May 17;102(20):7227-32; Haines JL, et al. Complement factor H variant increases the risk of age-related macular degeneration. 75 Science. 2005 Apr 15;308(5720):419-21 ; Klein RJ, et al Complement factor H polymorphism in age-related macular degeneration. Science. 2005 Apr
15;308(5720):385-9; Lau LI, et al. Association of the Y402H polymorphism in
complement factor H gene and neovascular age-related macular degeneration in
Chinese patients. Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3242-6; Simonelli F, et al.
80 Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age
related macular degeneration in an Italian population. Br J Ophthalmol. 2006
Sep;90(9):1 142-5; and Zareparsi S, et al Strong association of the Y402H variant in complement factor H at 1 q32with susceptibility to age-related macular degeneration. Am J Hum Genet. 2005 Jul;77(1 ):149-53. ), complement factor B (CFB) and complement C2
85 (Gold B, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006 Apr;38(4):458-62 and Jakobsdottir J, et al. C2 and CFB genes inage-related maculopathy and joint action with CFH and LOC387715 genes. PLoS One. 2008 May 21 ;3(5):e2199), and most recently in complement C3 (Despriet DD, et al Complement component C3 and risk of
90 age-related macular degeneration. Ophthalmology. 2009 Mar; 1 16(3):474-480.e2; Mailer JB, et al Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet. 2007 Oct;39(10):1200-1 and Park KH, et al Complement component 3 (C3) haplotypes and risk of advanced age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009 Jul;50(7):3386-93. Epub 2009 Feb 21 .). Taken together,
95 the genetic variations in the alternative pathway components CFH, CFB, and C3 can predict clinical outcome in nearly 80% of cases.
Currently there is no proven medical therapy for dry AMD and many patients with neovascular AMD become legally blind despite current therapy with anti-VEGF agents such as Lucentis. Thus, it would be desirable to provide therapeutic agents for the 100 treatment or prevention of complement mediated diseases and particularly for the
treatment of AMD.
SUMMARY OF THE DISCLOSURE
The present disclosure provides crystalline forms of 1 -(2-((1 R,3S,5R)-3-(((R)-1- (3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide:
Figure imgf000005_0001
Embodiments of these crystalline forms include those characterized herein as Forms A, B, C, D E and F. The names used herein to characterize a specific form, e.g. 110 "Form A", "Form B", "Form C", "Form D", "Form E" and "Form F", should not be
considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the
characterization information also presented herein.
115
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 . illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form A.
120 FIG. 2. illustrates the differential scanning calorimetry (DSC) of crystalline 1 -(2-
((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form A.
FIG. 3. illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3- 125 (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form B.
FIG. 4. illustrates the differential scanning calorimetry (DSC) of crystalline 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form 130 B.
FIG. 5. illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form C.
FIG. 6. illustrates the differential scanning calorimetry (DSC) of crystalline 1 -(2- 135 ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form C.
FIG. 7. illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- 140 oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form D.
FIG. 8. illustrates the differential scanning calorimetry (DSC) of crystalline 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form D.
145 FIG. 9. illustrates the x-ray powder diffraction patterns of 1-(2-((1 R,3S,5R)-3-
(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form E.
FIG. 10. illustrates the differential scanning calorimetry (DSC) of crystalline 1-(2-
((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- 150 azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form
E.
FIG. 1 1. illustrates the x-ray powder diffraction patterns of 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form F.
155 FIG. 12. illustrates the differential scanning calorimetry (DSC) of crystalline 1-(2-
((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide Form F.
160 DETAILED DESCRIPTION OF THE DISCLOSURE
The disclosure relates to crystalline forms of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro- 2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, which are described and characterized herein.
165 Definitions
As used herein "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
As used herein "solvate" refers to a crystalline form of a molecule, atom, and/or 170 ions that further comprises molecules of a solvent or solvents incorporated into the
crystalline lattice structure. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. For example, a solvate with a nonstoichiometric amount of solvent molecules may result from
175 partial loss of solvent from the solvate. Solvates may occur as dimers or oligomers
comprising more than one molecule or 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide within the crystalline lattice structure.
As used herein "amorphous" refers to a solid form of a molecule, atom, and/or
180 ions that is not crystalline. An amorphous solid does not display a definitive X-ray
diffraction pattern.
As used herein, "substantially pure," when used in reference to a form, means a compound having a purity greater than 90 weight %, including greater than 90 , 91 , 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight %
185 of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, a crystalline form of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-
190 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of 1-(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-
195 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide and/or reaction impurities and/or processing impurities.
Another way to define substantially pure is following:
As used herein, the term "substantially pure" with reference to a particular 200 polymorphic form means that the polymorphic form includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1 % by weight of any other physical forms of the compound.
In one embodiment of the disclosure, a crystalline form of the 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- 205 oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide is provided in substantially pure form. This crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other
210 components selected, for example, from the group consisting of excipients, carriers, and one of other active pharmaceutical ingredients active chemical entities of different molecular structure.
Preferably, the crystalline form has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 %
215 of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern. Most preferred is a crystalline form having substantially pure phase homogeneity with less than 1 % of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern.
220 In one embodiment, a composition is provided consisting essentially of the
crystalline form A of the 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide. The composition of this embodiment may comprise at least 90 weight % of the crystalline form A of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-
225 chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1-(2-((1 R,3S,5R)-3-(((R)- 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide in the composition.
In a first embodiment, the invention is a crystalline form of 1-(2-((1 R,3S,5R)-3-
230 (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide.
In a second embodiment, the invention is the crystalline form according to the first embodiment comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
235 pyrazolo[3,4-c]pyridine-3-carboxamide Form A.
In a third embodiment, the invention is the crystalline form according to the first and second embodiments consisting essentially of Form A.
In a fourth embodiment, the invention is the crystalline form according to first through the third embodiments wherein said Form A is in substantially pure form.
240 In a fifth embodiment, the invention is the crystalline form according to first
through fourth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of 4.72±0.2°, 5.88±0.2°, 8.40±0.2°, 10.41 ±0.2°, 1 1 .35±0.2°, 12.76±0.2°, 14.37±0.2°, 14.73±0.2°, 16.39±0.2°, 18.90±0.2°, 19.20±0.2°, 22.99±0.2° and 26.83±0.2°, at a temperature of
245 about 22°C. In a sixth embodiment, the invention is the crystalline form according to the fifth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values selected from the group consisting of 4.72±0.2°, 5.88±0.2°, 8.40±0.2°, 10.41 ±0.2°, 1 1.35±0.2°, 12.76±0.2°, 14.37±0.2°, 14.73±0.2°, 16.39±0.2°, 18.90±0.2°, 250 19.20±0.2°, 22.99±0.2° and 26.83±0.2°, at a temperature of about 22°C.
In a seventh embodiment, the invention is a crystalline form of 1 -(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1 .
255 In an eighth embodiment, the invention is a crystalline form of 1 -(2-((1 R,3S,5R)-3-
(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 2.
In a ninth embodiment, the invention is a pharmaceutical composition comprising 260 the crystalline form according the first through eighth embodiments and a
pharmaceutically acceptable carrier or diluent.
In a tenth embodiment, the invention is the pharmaceutical composition according to the ninth embodiment wherein said crystalline form is Form A.
In an eleventh embodiment, the invention is the pharmaceutical composition 265 according to the tenth embodiment wherein said Form A is in substantially pure form.
In a twelfth embodiment, the invention is a combination, in particular a
pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first through eighth embodiments and a second therapeutically active agent.
270 In a thirteenth embodiment, the invention is the pharmaceutical composition
according to the twelfth embodiment wherein said crystalline form is Form A.
In a fourteenth embodiment, the invention is the pharmaceutical composition according to the thirteenth embodiment wherein said Form A is in substantially pure form.
275 In a fifteenth embodiment, the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-
280 oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to first through eighth embodiments.
In a sixteenth embodiment, the invention is the method according to the fifteenth embodiment wherein said crystalline form is Form A.
In a seventeenth embodiment, the invention is the method according to the
285 sixteenth embodiment wherein said Form A is in substantially pure form.
In an eighteenth embodiment, the invention is the method according to the fifteenth embodiment wherein the subject is a human.
In a nineteenth embodiment, the invention is a composition comprising at least 90 weight % of the crystalline form according to the second through eighth embodiments
290 based on the weight of the composition.
In a twentieth embodiment, the invention is a process of making Form A of 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 1.
295 In one embodiment, a composition is provided consisting essentially of the
crystalline form B of the 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide. The composition of this embodiment may comprise at least 90 weight % of the crystalline form B of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-
300 chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1-(2-((1 R,3S,5R)-3-(((R)- 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide in the composition.
In a twenty first embodiment, the invention is the crystalline form according to the
305 first embodiment comprising 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide Form B.
In a twenty second embodiment, the invention is the crystalline form according to the first and twenty first embodiments consisting essentially of Form B.
310 In a twenty third embodiment, the invention is the crystalline form according to claims first and twenty first through twenty second embodiments wherein said Form B is in substantially pure form.
In a twenty fourth embodiment, the invention is the crystalline form according to the first and twenty first through twenty third embodiments characterized by a x-ray
315 powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of 7.37±0.2°, 7.84±0.2°, 9.18±0.2°, 1 1 .06±0.2°, 12.21 ±0.2°, 13.04±0.2°, 14.59±0.2°, 15.41 ±0.2°, 16.13±0.2°, 17.07±0.2°, 18.01 ±0.2°, 18.83±0.2°, 19.58±0.2°, 19.93±0.2°, 20.12±0.2°, 20.64±0.2°, 20.96±0.2°, 21 .36±0.2°, 22.07±0.2°, 22.60±0.2°, 22.99±0.2°, 24.46±0.2°, 24.83±0.2°, 25.25±0.2°, 25.85±0.2°, 26.61 ±0.2°, 27.07±0.2°, 320 27.54±0.2°, 28.33±0.2° and 29.53±0.2°, at a temperature of about 22°C.
In a twenty fifth embodiment, the invention is the crystalline form according to the twenty fourth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 20 values selected from the group consisting of 7.37±0.2°, 7.84±0.2°, 9.18±0.2°, 1 1 .06±0.2°, 12.21 ±0.2°, 13.04±0.2°, 14.59±0.2°, 15.41 ±0.2°, 325 16.13±0.2°, 17.07±0.2°, 18.01 ±0.2°, 18.83±0.2°, 19.58±0.2°, 19.93±0.2°, 20.12±0.2°, 20.64±0.2°, 20.96±0.2°, 21 .36±0.2°, 22.07±0.2°, 22.60±0.2°, 22.99±0.2°, 24.46±0.2°, 24.83±0.2°, 25.25±0.2°, 25.85±0.2°, 26.61 ±0.2°, 27.07±0.2°, 27.54±0.2°, 28.33±0.2° and 29.53±0.2°, at a temperature of about 22°C.
In a twenty sixth embodiment, the invention is a crystalline form of 1-(2- 330 ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 3.
In a twenty seventh embodiment, the invention a crystalline form of 1 -(2- 335 ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 4.
In a twenty seventh embodiment, the invention is a pharmaceutical composition 340 comprising the crystalline form according to first and twenty first through the twenty seventh embodiments and a pharmaceutically acceptable carrier or diluent.
In a twenty ninth embodiment, the invention is the pharmaceutical composition according to the twenty eighth embodiment wherein said crystalline form is Form B.
In a thirtieth embodiment, the invention is the pharmaceutical composition 345 according to the twenty ninth embodiment wherein said Form B is in substantially pure form.
In a thirty first embodiment, the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of first and twenty first through the twenty seventh 350 embodiments and a second therapeutically active agent.
In a thirty second embodiment, the invention is the pharmaceutical composition according to the thirty first embodiment wherein said crystalline form is Form B.
In a thirty third embodiment, the invention is the pharmaceutical composition according to the thirty second embodiment wherein said Form B is in substantially pure 355 form.
In a thirty fourth embodiment, the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1 -(2-((1 R,3S,5R)-3-
360 (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to any one of first and twenty first through the twenty seventh embodiments.
In a thirty fifth embodiment, the invention is the method according to the thirty fourth embodiment wherein said crystalline form is Form B.
365 In a thirty sixth embodiment, the invention is the method according to the thirty fifth embodiment wherein said Form B is in substantially pure form.
In a thirty seventh embodiment, the invention is the method according to the thirty fourth embodiment wherein the subject is a human.
In a thirty eighth embodiment, the invention is a composition comprising at least
370 90 weight % of the crystalline form according to any one of first and twenty first through the twenty seventh embodiments, based on the weight of the composition.
In a thirty ninth embodiment, the invention is a process of making Form B of 1-(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide
375 comprising the steps of Example 2.
In one embodiment, a composition is provided consisting essentially of the crystalline form C of the 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide. The composition of this embodiment may
380 comprise at least 90 weight % of the crystalline form C of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1-(2-((1 R,3S,5R)-3-(((R)- 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide in the composition.
385 In a fortieth embodiment, the invention is the crystalline form according to the first embodiment comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide Form C.
In a forty second embodiment, the invention is the crystalline form according to
390 the first and fortieth embodiments consisting essentially of Form C.
In a forty third embodiment, the invention is the crystalline form according to first and fortieth through forty first embodiments wherein said Form C is in substantially pure form. In a forty third embodiment, the invention is the crystalline form according to the
395 first and fortieth through forty third embodiments characterized by a x-ray powder
diffraction pattern comprising four or more 2Θ values selected from the group consisting of 6.93±0.2°, 8.83±0.2°, 10.58±0.2°, 1 1 .56±0.2°, 12.98±0.2°, 13.56±0.2°, 14.04±0.2°, 14.60±0.2°, 14.85±0.2°, 16.65±0.2°, 17.41 ±0.2°, 17.77±0.2°, 18.46±0.2°, 19.54±0.2°, 21.38±0.2°, 22.03±0.2°, 22.75±0.2°, 24.53±0.2°, 25.1 1 ±0.2°, 25.77±0.2°, 26.62±0.2°,
400 27.47±0.2°, 29.41 ±0.2° and 29.88±0.2°, at a temperature of about 22°C.
In a forty fourth embodiment, the invention is the crystalline form according to claim 43 further characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values selected from the group consisting of 6.93±0.2°, 8.83±0.2°, 10.58±0.2°, 1 1.56±0.2°, 12.98±0.2°, 13.56±0.2°, 14.04±0.2°, 14.60±0.2°, 14.85±0.2°, 16.65±0.2°,
405 17.41 ±0.2°, 17.77±0.2°, 18.46±0.2°, 19.54±0.2°, 21 .38±0.2°, 22.03±0.2°, 22.75±0.2°,
24.53±0.2°, 25.1 1 ±0.2°, 25.77±0.2°, 26.62±0.2°, 27.47±0.2°, 29.41 ±0.2° and 29.88±0.2°, at a temperature of about 22°C.
In a forty fifth embodiment, the invention is a crystalline form of 1 -(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-
410 oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 5.
In a forty sixth embodiment, the invention is a crystalline form of 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide
415 having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 6.
In a forty seventh embodiment, the invention is a pharmaceutical composition comprising the crystalline form according to the first and fortieth through forty sixth embodiments and a pharmaceutically acceptable carrier or diluent.
420 In a forty eighth embodiment, the invention is the pharmaceutical composition according to the forty seventh embodiment wherein said crystalline form is Form C.
In a forty ninth embodiment, the invention is the pharmaceutical composition according to the forty eighth embodiment wherein said Form C is in substantially pure form.
425 In a fiftieth embodiment, the invention is a combination, in particular a
pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first and fortieth through forty sixth embodiments and a second therapeutically active agent.
In a fifty first embodiment, the invention is the pharmaceutical composition
430 according to the fiftieth embodiment wherein said crystalline form is Form C. In a fifty second embodiment, the invention is the pharmaceutical composition according to the fifty first embodiment wherein said Form C is in substantially pure form.
In a fifty third embodiment, the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by 435 activation of the complement alternative pathway, comprising administering to the
mammal a therapeutically-effective amount of a crystalline form of 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to the first and fortieth through forty sixth embodiments.
440 In a fifty fourth embodiment, the invention is the method according to the fifty third embodiment wherein said crystalline form is Form C.
In a fifty fifth embodiment, the invention is the method according to the fifty fourth embodiment wherein said Form C is in substantially pure form.
In a fifty sixth embodiment, the invention is the method according to the fifty third 445 embodiment wherein the subject is a human.
In a fifty seventh embodiment, the invention is a composition comprising at least 90 weight % of the crystalline form according to the first and fortieth through forty sixth embodiments, based on the weight of the composition.
In a fifty eighth embodiment, the invention is a process of making Form C of 1 -(2- 450 ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 3.
In one embodiment, a composition is provided consisting essentially of the crystalline form D of the 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- 455 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide. The composition of this embodiment may comprise at least 90 weight % of the crystalline form D of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1-(2-((1 R,3S,5R)-3-(((R)- 460 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide in the composition.
In a fifty ninth embodiment, the invention is the crystalline form according to the first embodiment comprising 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- 465 pyrazolo[3,4-c]pyridine-3-carboxamide Form D.
In a sixtieth embodiment, the invention is the crystalline form according to first and fifty ninth embodiments consisting essentially of Form D. In a sixty first embodiment, the invention is the crystalline form according to the first and fifty ninth through sixtieth embodiments wherein said Form D is in substantially 470 pure form.
In a sixty second embodiment, the invention is the crystalline form according to the first and fifty ninth through sixty first embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of 6.03±0.2°, 7.23±0.2°, 7.79±0.2°, 8.19±0.2°, 9.26±0.2°, 10.85±0.2°, 1 1 .63±0.2°, 475 12.62±0.2°, 12.95±0.2°, 13.66±0.2°, 14.17±0.2°, 14.71 ±0.2°, 15.31 ±0.2°, 16.14±0.2°, 17.15±0.2°, 17.55±0.2°, 18.33±0.2°, 19.16±0.2°, 19.69±0.2°, 20.27±0.2°, 21.82±0.2°, 22.45±0.2°, 23.43±0.2°, 25.05±0.2°, 27.48±0.2°, 28.35±0.2°, 28.76±0.2° and 29.56±0.2°, at a temperature of about 22°C.
In a sixty third embodiment, the invention is the crystalline form according to the 480 sixty second embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values selected from the group consisting of 6.03±0.2°, 7.23±0.2°, 7.79±0.2°, 8.19±0.2°, 9.26±0.2°, 10.85±0.2°, 1 1.63±0.2°, 12.62±0.2°, 12.95±0.2°, 13.66±0.2°, 14.17±0.2°, 14.71 ±0.2°, 15.31 ±0.2°, 16.14±0.2°, 17.15±0.2°, 17.55±0.2°, 18.33±0.2°, 19.16±0.2°, 19.69±0.2°, 20.27±0.2°, 21.82±0.2°, 22.45±0.2°, 485 23.43±0.2°, 25.05±0.2°, 27.48±0.2°, 28.35±0.2°, 28.76±0.2° and 29.56±0.2°, at a
temperature of about 22°C.
In a sixty fourth embodiment, the invention is a crystalline form of 1-(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide 490 having a X-ray diffraction spectrum substantially the same as the X-ray powder
diffraction spectrum shown in FIG. 7.
In a sixty fifth embodiment, the invention is a crystalline form of 1-(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning 495 calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 8.
In a sixty sixth embodiment, the invention is a pharmaceutical composition comprising the crystalline form according to the first and fifty ninth through sixty fifth embodiments and a pharmaceutically acceptable carrier or diluent.
In a sixty seventh embodiment, the invention is the pharmaceutical composition 500 according to the sixty sixth embodiment wherein said crystalline form is Form D.
In a sixty eighth embodiment, the invention is the pharmaceutical composition according to the sixty seventh embodiment wherein said Form D is in substantially pure form.
In a sixty ninth embodiment, the invention is a combination, in particular a 505 pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first and fifty ninth through sixty fifth embodiments and a second therapeutically active agent.
In a seventieth embodiment, the invention is the pharmaceutical composition according to the sixty ninth embodiment wherein said crystalline form is Form D.
510 In a seventy first embodiment, the invention is the pharmaceutical composition according to the seventieth embodiment wherein said Form D is in substantially pure form.
In a seventy second embodiment, the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by 515 activation of the complement alternative pathway, comprising administering to the
mammal a therapeutically-effective amount of a crystalline form of 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to the first and fifty ninth through sixty fifth embodiments.
520 In a seventy third embodiment, the invention is the method according to the
seventy second embodiment wherein said crystalline form is Form D.
In a seventy fourth embodiment, the invention is the method according to the seventy third embodiment wherein said Form D is in substantially pure form.
In a seventy fifth embodiment, the invention is the method according to the 525 seventy second embodiment wherein the subject is a human.
In a seventy sixth embodiment, the invention is a composition comprising at least 90 weight % of the crystalline form according to the first and fifty ninth through sixty fifth embodiments based on the weight of the composition.
In a seventy seventh embodiment, the invention is a process of making Form D of 530 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 4.
In one embodiment, a composition is provided consisting essentially of the crystalline form E of the 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- 535 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide. The composition of this embodiment may comprise at least 90 weight % of the crystalline form E of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1-(2-((1 R,3S,5R)-3-(((R)- 540 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide in the composition. In a seventy eighth embodiment, the invention is the crystalline form according to the first embodiment comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- 545 pyrazolo[3,4-c]pyridine-3-carboxamide Form E.
In a seventy ninth embodiment, the invention is the crystalline form according to the first and seventy eighth embodiments consisting essentially of Form E.
In an eightieth embodiment, the invention is the crystalline form according to the first and seventy eighth through seventy ninth embodiments wherein said Form E is in 550 substantially pure form.
In an eighty first embodiment, the invention is the crystalline form according to the first and seventy eighth through eightieth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of 4.76±0.2°, 7.67±0.2°, 8.56±0.2°, 10.45±0.2°, 13.24±0.2°, 13.89±0.2°, 14.63±0.2°, 555 14.96±0.2°, 15.53±0.2°, 16.13±0.2°, 16.51 ±0.2°, 17.63±0.2°, 19.06±0.2°, 21.95±0.2°, 22.43±0.2°, 25.97±0.2°, 26.95±0.2° and 27.80±0.2°, at a temperature of about 22°C.
In an eighty second embodiment, the invention is the crystalline form according to the eighty first embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values selected from the group consisting of 4.76±0.2°, 560 7.67±0.2°, 8.56±0.2°, 10.45±0.2°, 13.24±0.2°, 13.89±0.2°, 14.63±0.2°, 14.96±0.2°,
15.53±0.2°, 16.13±0.2°, 16.51 ±0.2°, 17.63±0.2°, 19.06±0.2°, 21.95±0.2°, 22.43±0.2°, 25.97±0.2°, 26.95±0.2° and 27.80±0.2°, at a temperature of about 22°C.
In a an eighty third embodiment, the invention is a crystalline form of 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- 565 azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide
having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 9.
In an eighty fourth embodiment, the invention is a crystalline form of 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- 570 azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide
having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 10.
In an eighty fifth embodiment, the invention is a pharmaceutical composition comprising the crystalline form according to the first and seventy eighth through eighty 575 fourth embodiments and a pharmaceutically acceptable carrier or diluent.
In an eighty sixth embodiment, the invention is the pharmaceutical composition according to the eighty fifth embodiment wherein said crystalline form is Form E.
In an eighty seventh embodiment, the invention is the pharmaceutical composition according to the eighty sixth embodiment wherein said Form E is in 580 substantially pure form.
In an eighty eighth embodiment, the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first and seventy eighth through eighty fourth embodiments and a second therapeutically active agent.
585 In an eighty ninth embodiment, the invention is the pharmaceutical composition according to the eighty eighth embodiment wherein said crystalline form is Form E.
In a ninetieth embodiment, the invention is the pharmaceutical composition according to the eighty ninth embodiment wherein said Form E is in substantially pure form.
590 In a ninety first embodiment, the invention is a method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-
595 oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to the first and seventy eighth through eighty fourth embodiments.
In a ninety second embodiment, the invention is the method according to the ninety first embodiment wherein said crystalline form is Form E.
In a ninety third embodiment, the invention is the method according to the ninety
600 second embodiment wherein said Form E is in substantially pure form.
In a ninety fourth embodiment, the invention is the method according to ninety first embodiment wherein the subject is a human.
In a ninety fifth embodiment, the invention is acomposition comprising at least 90 weight % of the crystalline form according to the first and seventy eighth through eighty
605 fourth embodiments based on the weight of the composition.
In a ninety sixth embodiment, the invention is a process of making Form E of 1 - (2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 5.
610 In one embodiment, a composition is provided consisting essentially of the
crystalline form F of the 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide. The composition of this embodiment may comprise at least 90 weight % of the crystalline form F of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-
615 chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, based on the weight of 1-(2-((1 R,3S,5R)-3-(((R)- 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide in the composition.
In a ninety seventh embodiment, the invention is the crystalline form according to the first embodiment comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide Form F.
In a ninety eighth embodiment, the invention is the crystalline form according to the first and ninety seventh embodiments consisting essentially of Form F.
In a ninety ninth embodiment, the invention is the crystalline form according to the first and ninety seventh through ninety eighth embodiments wherein said Form F is in substantially pure form.
In a hundredth embodiment, the invention is the crystalline form according to the first and ninety seventh through ninety ninth embodiments characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of 6.91 ±0.2°, 7.99±0.2°, 8.85±0.2°, 9.64±0.2°, 10.58±0.2°, 1 1.80±0.2°, 13.60±0.2°, 14.74±0.2°, 15.15±0.2°, 16.77±0.2°, 17.46±0.2°, 18.07±0.2°, 18.64±0.2°, 19.07±0.2°, 20.45±0.2°, 21 .52±0.2°, 21 .89±0.2°, 23.45±0.2°, 26.10±0.2°, 26.76±0.2°, 27.62±0.2° and 27.89±0.2°, at a temperature of about 22°C.
In a hundred first embodiment, the invention is the crystalline form according to hundredth embodiment further characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values selected from the group consisting of 6.91 ±0.2°, 7.99±0.2°, 8.85±0.2°, 9.64±0.2°, 10.58±0.2°, 1 1.80±0.2°, 13.60±0.2°, 14.74±0.2°, 15.15±0.2°, 16.77±0.2°, 17.46±0.2°, 18.07±0.2°, 18.64±0.2°, 19.07±0.2°, 20.45±0.2°, 21.52±0.2°, 21.89±0.2°, 23.45±0.2°, 26.10±0.2°, 26.76±0.2°, 27.62±0.2° and 27.89±0.2°, at a temperature of about 22°C.
In a hundred second embodiment, the invention is a crystalline form of 1-(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1 1 .
In a hundred third embodiment, the invention is a crystalline form of 1-(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 12.
In a hundred fourth embodiment, the invention is a pharmaceutical composition comprising the crystalline form according to the first and ninety seventh through the hundred third embodiments and a pharmaceutically acceptable carrier or diluent.
655 In a hundred fifth embodiment, the invention is the pharmaceutical composition according to the hundred fourth embodiment wherein said crystalline form is Form F.
In a hundred sixth embodiment, the invention is the pharmaceutical composition according to the hundred fifth embodiment wherein said Form F is in substantially pure form.
660 In a hundred seventh embodiment, the invention is a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of the first and ninety seventh through the hundred third embodiments and a second therapeutically active agent.
In a hundred eighth embodiment, the invention is the pharmaceutical composition 665 according to the hundred seventh embodiment wherein said crystalline form is Form F.
In a hundred ninth embodiment, the invention is the pharmaceutical composition according to the hundred eighth embodiment wherein said Form F is in substantially pure form.
In a hundred tenth embodiment, the invention is a method of treating a disorder 670 or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1 -(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to the first and ninety 675 seventh through the hundred third embodiments.
In a hundred eleventh embodiment, the invention is the method according to the hundred tenth embodiment wherein said crystalline form is Form F.
In a hundred twelfth embodiment, the invention is the method according to the hundred eleventh embodiment wherein said Form F is in substantially pure form.
680 In a hundred thirteenth embodiment, the invention is the method according to the hundred tenth embodiment wherein the subject is a human.
In a hundred fourteenth embodiment, the invention is a composition comprising at least 90 weight % of the crystalline form according to the first and ninety seventh through the hundred third embodiments based on the weight of the composition.
685 In a hundred fifteenth embodiment, the invention is a process of making Form A of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 6.
The presence of reaction impurities and/or processing impurities may be 690 determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy.
The present invention provides a crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
695 pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.
The term "essentially the same" with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2Θ) will show some
700 inter-apparatus variability, typically as much as 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.
705 Preparation of Crystalline Materials:
Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of
710 crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including
715 polymorphs.
Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999).
For crystallization techniques that employ solvent, the choice of solvent or
720 solvents is typically dependent upon one or more factors, such as solubility of the
compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals. An
725 antisolvent is a solvent in which the compound has low solubility.
In one method to prepare crystals, a compound is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution. The term "slurry", as used herein, means a saturated solution of the compound, which may also contain an additional amount of the compound to afford a heterogeneous mixture of the compound
730 and a solvent at a given temperature.
Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an
735 average product particle as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971 ,26, 369- 377. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions. Care should be
740 taken that milling or micronizing of crystals does not result in any change in crystallinity form the desired crystal form (i.e., change to amorphous or to another polymorph).
A cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form. The isolated solids
745 may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the
750 weight of the compound originally employed in the crystallization procedure. The product may be comilled or passed through a mesh screen to delump the product, if necessary.
Crystalline forms may be prepared directly from the reaction medium of the final process for preparing 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
755 pyrazolo[3,4-c]pyridine-3-carboxamide This may be achieved, for example, by employing in the final process step a solvent or a mixture of solvents from which 1-(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide may be crystallized. Alternatively, crystalline forms may be obtained by distillation or solvent addition techniques. Suitable
760 solvents for this purpose include, for example, the aforementioned nonpolar solvents and polar solvents, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.
The presence of more than one polymorph in a sample may be determined by techniques such as x-ray powder diffraction (PXRD) or solid state nuclear magnetic 765 resonance spectroscopy. For example, the presence of extra peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern may indicate more than one polymorph in the sample. The simulated PXRD may be calculated from single crystal x-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, 770 UCRL-7196 (April 1963) or TOPAS program (Total Pattern Analysis Solution, available through Brucker AXS Inc.).
Various analytical methods may be used for characterization.
I. X-ray Powder Diffraction Measurements
One of ordinary skill in the art will appreciate that an X-ray diffraction pattern may
775 be obtained with a measurement error that is dependent upon the measurement
conditions employed. In particular, it is generally known that intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken
780 into account. Additionally, a measurement error of diffraction angle for a conventional X- ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to
785 the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein.
Any crystal forms that provide X- ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.
790 II. Differential Scanning Calorimetry (DSC)
The DSC instrument used to test the crystalline forms was a TA Instrument® Differential Scanning Calorimetry Model 2910, TA Instruments® Modulated Differential Scanning Calorimetry Model 2920, or TA Instruments® Modulated Differential Scanning Calorimetry Model Q1000. The DSC cell/sample chamber was purged with 100 ml/min of
795 ultra-high purity nitrogen gas. The instrument was calibrated with high purity indium. The accuracy of the measured sample temperature with this method is within about ± 1 °C, and the heat of fusion can be measured within a relative error of about ±5%. The sample was placed into an open aluminum DSC pan and measured against an empty reference pan. About 2-6 mg of sample powder was placed into the bottom of the pan and lightly
800 tapped down to make contact with the pan. The weight of the sample was measured accurately and recorded to a hundredth of a milligram. The instrument was programmed to heat at 10°C. per minute in the temperature range between 25 and 300°C.
The heat flow, which was normalized by a sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram ("W/g"). 805 The plot was made with the endothermic peaks pointing down. The endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.
III. Thermogravimetric Analysis (TGA)
The TGA instruments used to test the crystalline forms was a TA
810 Instruments. RTM. High Resolution Thermogravimetric Analyzer Q500 or TA
Instruments. RTM. High Resolution Thermogravimetric Analyzer 2950. Samples of 15 to
20 milligrams were analyzed at a heating rate of 10°C per minute in the temperature range between 25°C and about 300°C.
Utility
815 In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and ophthalmic administration, etc. In addition, the pharmaceutical compositions of the present invention
820 can be made up in a solid form (including without limitation capsules, tablets, pills,
granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions, emulsions, each of which may be suitable for ophthalmic administration). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert
825 diluents, lubricating agents, or buffering agents, as well as adjuvants, such as
preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with
a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose 830 and/or glycine;
b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also
c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or
835 polyvinylpyrrolidone; if desired
d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
Tablets may be either film coated or enteric coated according to methods known 840 in the art.
Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the
845 art for the manufacture of pharmaceutical compositions and such compositions can
contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are
850 suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by
855 known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium
860 phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving,
865 stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
870 Suitable compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally 875 with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g.,
880 for delivery by aerosol or the like. Such topical delivery systems will in particular be
appropriate for ophthalmic application, e.g., for the treatment of eye diseases e.g., for therapeutic or prophylactic use in treating age related macular degeneration and other complement mediated ophthalmic disorders. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
885 As used herein a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or
890 without the use of a suitable propellant.
Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants
895 that may be desirable.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
900 Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
905 Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active
910 compound in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active
915 ingredients, since water may facilitate the degradation of certain compounds.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous
920 compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
The invention further provides pharmaceutical compositions and dosage forms
925 that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
Prophylactic and Therapeutic Uses
930 The physical forms of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. Factor D modulating properties, complement pathway modulating properties and modulation of the complement
935 alternative pathway properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
The present invention provides methods of treating a disease or disorder associated with increased complement activity by administering to a subject in need thereof an effective amount of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-
940 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide of the invention. In certain aspects, methods are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway. In certain embodiments, methods of treating or preventing compelment mediated diseases are provided in which the
945 complement activation is induced by antibody-antigen interactions, by a component of an autoimmune disease, or by ischemic damage.
In a specific embodiment, the present invention provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of 1 -(2-((1 R,3S,5R)-3-((2-fluoro-31 -(2-((1 R,3S,5R)-3-
950 (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide In certain embodiments, patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration related disorder are suitable for administration with a compound of the invention. The methods of treating or preventing AMD include, but are not limited to,
955 methods of treating or preventing one or more symptoms or aspects of AMD selected from formation of ocular drusen, inflammation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including loss of visual acuity or visual field), neovascularization (including CNV), retinal detachment, photoreceptor degeneration, RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration,
960 retinal dysfunction, retinal damage in response to light exposure, damage of the Bruch's membrane, and/ or loss of RPE function.
1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide can be used, inter alia, to prevent the onset of AMD, to prevent the progression of early AMD
965 to advanced forms of AMD including neovascular AMD or geographic atrophy, to slow and/or prevent progression of geographic atrophy, to treat or prevent macular edema from AMD or other conditions (such as diabetic retinopathy, uveitis, or post surgical or non-surgical trauma), to prevent or reduce the loss of vision from AMD, and to improve vision lost due to pre-existing early or advanced AMD. It can also be used in
970 combination with anti-VEGF therapies for the treatment of neovascular AMD patients or for the prevention of neovascular AMD. The present invention further provides methods of treating a complement related disease or disorder by administering to a subject in need thereof an effective amount of the compound(s) of the invention, wherein said disease or disorder is selected from uveitis, adult macuar degeneration, diabetic
975 retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, and retinal vein occlusion.
In some embodiments, the present invention provides methods of treating a
980 complement related disease or disorder by administering to a subject in need thereof an effective amount of the compounds of the invention. Examples of known complement related diseases or disorders include: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications,
985 hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL- 2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass,
990 atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration and neural regeneration. In addition, other known complement related 995 disease are lung disease and disorders such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen
1000 sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze), asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, uveitis (including Behcet's disease and other sub-types of uveitis), antiphospholipid syndrome.
1005 In a specific embodiment, the present invention provides methods of treating a complement related disease or disorder by administering to a subject in need thereof an effective amount of the compounds of the invention, wherein said disease or disorder is asthma, arthritis (e.g., rheumatoid arthritis), autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injuries, Barraquer-Simons
1010 Syndrome, hemodialysis, systemic lupus, lupus erythematosus, psoriasis, multiple
sclerosis, transplantation, diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions, atypicaly hemolytic uremic syndrome (aHUS), glomerulonephritis (including membrane proliferative glomerulonephritis), blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and
1015 epidermolysis bullosa), ocular cicatrical pemphigoid or MPGN II.
In a specific embodiment, the present invention provides methods of treating glomerulonephritis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the present invention. Symptoms of
glomerulonephritis include, but not limited to, proteinuria; reduced glomerular filtration
1020 rate (GFR); serum electrolyte changes including azotemia (uremia, excessive blood urea nitrogen-BUN) and salt retention, leading to water retention resulting in hypertension and edema; hematuria and abnormal urinary sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and lipiduria. In a specific embodiment, the present invention provides methods of treating paroxysmal nocturnal hemoglobinuria (PNH) by
1025 administering to a subject in need thereof an effective amount of a composition
comprising an compound of the present invention with or without concomitent administration of a complement C5 inhibitor or C5 convertase inhibitor such as Soliris.
In a specific embodiment, the present invention provides methods of reducing the dysfunction of the immune and/or hemostatic systems associated with extracorporeal
1030 circulation by administering to a subject in need thereof an effective amount of a
composition comprising an compound of the present invention. 1-(2-((1 R,3S,5R)-3-(((R)- 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide can be used in any procedure which involves circulating the patient's blood from a blood vessel of the patient, through a conduit, and
1035 back to a blood vessel of the patient, the conduit having a luminal surface comprising a material capable of causing at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte adhesion. Such procedures include, but are not limited to, all forms of ECC, as well as procedures involving the introduction of an artificial or foreign organ, tissue, or vessel into the blood circuit of a patient. More
1040 particularly, such procedures include, but are not limited to, transplantation procedures including kidney, liver, lung or heart transplant procedures and islet cell transplant procedures.
In other embodiments, the compounds of the invention are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including
1045 obesity and other metabolic disorders.
In another embodiment, the compounds of the invention may be used in blood ampules, diagnostic kits and other equipment used in the collection and sampling of blood. The use of the compounds of the invention in such diagnostic kits may inhibit the ex vivo activation of the complement pathway associated with blood sampling.
1050 The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1 -1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1 -500 mg or about 1 -250 mg or about 1 -150 mg or about 0.5-100 mg, or about 1 -50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of
1055 the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease. The above-cited dosage properties are demonstrable in vitro and in vivo tests 1060 using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10"3 molar and 10"9 1065 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1 -500 mg/kg, or between about 1-100 mg/kg.
The activity of a compound according to the present invention can be assessed by the following in vitro & in vivo methods.
1070 The compound of the present invention may be administered either
simultaneously with, or before or after, one or more other therapeutic agent. The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
1075 In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by alternative complement pathway. Products provided as a combined preparation include a composition comprising 1 -(2-
1080 ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide and the other therapeutic agent(s) together in the same pharmaceutical composition, or 1 1 - (2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide and
1085 the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
In one embodiment, the invention provides a pharmaceutical composition comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise
1090 a pharmaceutically acceptable excipient, as described above.
In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains 1 -(2-((1 R,3S,5R)-3-(((R)-1- (3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide. In one embodiment, the kit comprises means for
1095 separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different
1 100 dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.
In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other
1 105 therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient
themselves, e.g. during sequential administration of the compound of the invention and
1 1 10 the other therapeutic agent.
Accordingly, the invention provides the use of 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide for treating a disease or condition mediated by the complement alternative pathway, wherein the medicament is prepared for
1 1 15 administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the
complement alternative pathway, wherein the medicament is administered with 1 -(2- ((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide.
1 120 The invention also provides 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide for use in a method of treating a disease or condition mediated by the complement alternative pathway, wherein 1 1 -(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-
1 125 oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor D, wherein the other therapeutic agent is prepared for
administration with 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-
1 130 2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide.
The invention also provides 1 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor D, wherein 1 -
1 135 (2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor D, wherein the other therapeutic agent is
1 140 administered with 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)- 2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide.
The invention also provides the use of 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide for treating a disease or condition mediated by
1 145 the complement alternative pathway and/or Factor D, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the complement alternative pathway and/or Factor D wherein the patient has previously (e.g. within 24 hours) been treated with 1 -(2-((1 R,3S,5R)-3-(((R)-1 -(3-
1 150 chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
The pharmaceutical compositions can be administered alone or in combination with other molecules known to have a beneficial effect on retinal attachment or damaged retinal tissue, including molecules capable of tissue repair and regeneration and/or
1 155 inhibiting inflammation. Examples of useful, cofactors include anti-VEGF agents (such as an antibody or FAB against VEGF, e.g., Lucentis or Avastin), basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), axokine (a mutein of CNTF), leukemia inhibitory factor (LI F), neutrotrophin 3 (NT-3), neurotrophin-4 (NT-4), nerve growth factor (NGF), insulin-like growth factor I I, prostaglandin E2, 30 kD survival factor, taurine, and
1 160 vitamin A. Other useful cofactors include symptom-alleviating cofactors, including
antiseptics, antibiotics, antiviral and antifungal agents and analgesics and
anestheticsSuitable agents for combination treatment with the compounds of the invention include agents known in the art that are able to modulate the activities of complement components.
1 165 A combination therapy regimen may be additive, or it may produce synergistic results (e.g., reductions in complement pathway activity more than expected for the combined use of the two agents). In some embodiments, the present invention provide a combination therapy for preventing and/or treating AMD or another complement related ocular disease as described above with a compound of the invention and an anti- 1170 angiogenic, such as anti-VEGF agent (including Lucentis and Avastin) or photodynamic therapy (such as verteporfin).
In some embodiments, the present invention provide a combination therapy for preventing and/or treating autoimmune disease as described above with a compound of the invention and a B-Cell or T-Cell modulating agent (for example cyclosporine or
1175 analogs thereof, rapamycin, RAD001 or analogs thereof, and the like). In particular, for multiple sclerosis therapy may include the combination of a compound of the invention and a second MS agent selected from fingolimod, cladribine, tysarbi, laquinimod, rebif, avonex and the like.
In one embodiment, the invention provides a method of modulating activity of the
1180 complement alternative pathway in a subject, wherein the method comprises
administering to the subject a therapeutically effective amount of 1-(2-((1 R,3S,5R)-3- (((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide. The invention further provides methods of modulating the activity of the complement alternative pathway in a subject by
1185 modulating the activity of Factor D, wherein the method comprises administering to the subject a therapeutically effective amount of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
In one embodiment, the invention provides 1-(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-
1190 2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, for use as a medicament.
In one embodiment, the invention provides the use of 1 -(2-((1 R,3S,5R)-3-(((R)-1 - (3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, for the treatment of a disorder or disease in a
1195 subject mediated by complement activation. In particular, the invention provides the use of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide, for the treatment of a disorder or disease mediated by activation of the complement alternative pathway.
1200 In one embodiment, the invention provides the use of 1 -(2-((1 R,3S,5R)-3-(((R)-1 -
(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide, in the manufacture of a medicament for the treatment of a disorder or disease in a subject characterized by activation of the complement system. More particularly in the manufacture of a medicament for the
1205 treatment of a disease or disorder in a subject characterized by over activiation of the complement alternative pathway. In one embodiment, the invention provides the use of 1 1-(2-((1 R,3S,5R)-3-(((R)- 1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for the treatment of a disorder or disease in a
1210 subject characterized by activation of the complement system. More particularly, the invention provides uses of the compounds provided herein in the treatment of a disease or disorder characterized by over activiation of the complement alternative pathway or the C3 amplification loop of the alternative pathway. In certain embodiments, the use is in the treatment of a disease or disorder is selected from retinal diseases (such as age-
1215 related macular degeneration).
The present invention provides use of the compounds of the invention for treating a disease or disorder associated with increased complement activity by administering to a subject in need thereof an effective amount of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
1220 pyrazolo[3,4-c]pyridine-3-carboxamide. In certain aspects, uses are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway. In certain embodiments, uses of treating or preventing compelment mediated diseases are provided in which the complement activation is induced by antibody-antigen interactions, by a component of an autoimmune disease, or
1225 by ischemic damage.
In a specific embodiment, the present invention provides use of the compounds of the invention for treating or preventing age-related macular degeneration (AMD). In certain embodiments, patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration related disorder are suitable for
1230 administration with a compound of the invention. The use in treating or preventing AMD include, but are not limited to, uses in treating or preventing one or more symptoms or aspects of AMD selected from formation of ocular drusen, inflammation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including loss of visual acuity or visual field), neovascularization (including CNV), retinal detachment, photoreceptor
1235 degeneration, RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, retinal damage in response to light exposure, damage of the Bruch's membrane, and/ or loss of RPE function.
1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide can
1240 be used, inter alia, to prevent the onset of AMD, to prevent the progression of early AMD to advanced forms of AMD including neovascular AMD or geographic atrophy, to slow and/or prevent progression of geographic atrophy, to treat or prevent macular edema from AMD or other conditions (such as diabetic retinopathy, uveitis, or post surgical or non-surgical trauma), to prevent or reduce the loss of vision from AMD, and to improve
1245 vision lost due to pre-existing early or advanced AMD. It can also be used in
combination with anti-VEGF therapies for the treatment of neovascular AMD patients or for the prevention of neovascular AMD. The present invention further provides methods of treating a complement related disease or disorder by administering to a subject in need thereof an effective amount of the compound(s) of the invention, wherein said
1250 disease or disorder is selected from uveitis, adult macuar degeneration, diabetic
retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, and retinal vein occlusion.
1255 In some embodiments, the present invention provides uses for treating a
complement related disease or disorder. Examples of known complement related diseases or disorders include: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft
1260 rejection, xenograft rejection, interleukin-2 induced toxicity during I L-2 therapy,
inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post- pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis,
1265 hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration and neural regeneration. In addition, other known complement related disease are lung
1270 disease and disorders such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide,
1275 nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze), asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, uveitis (including Behcet's disease and other sub-types of uveitis), antiphospholipid syndrome.
1280 In a specific embodiment, the present invention provides use of 1 -(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 ]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for treating a complement related disease or disorder, wherein said disease or disorder is asthma, arthritis (e.g., rheumatoid arthritis), autoimmune heart disease, multiple sclerosis, inflammatory bowel
1285 disease, ischemia-reperfusion injuries, Barraquer-Simons Syndrome, hemodialysis, systemic lupus, lupus erythematosus, psoriasis, multiple sclerosis, transplantation, diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions, atypicaly hemolytic uremic syndrome (aHUS),
glomerulonephritis (including membrane proliferative glomerulonephritis), blistering
1290 cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis
bullosa), ocular cicatrical pemphigoid or MPGN II.
In a specific embodiment, the present invention provides use of 1 -(2-((1 R,3S,5R)- 3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for treating glomerulonephritis.
1295 Symptoms of glomerulonephritis include, but not limited to, proteinuria; reduced
glomerular filtration rate (GFR); serum electrolyte changes including azotemia (uremia, excessive blood urea nitrogen-BUN) and salt retention, leading to water retention resulting in hypertension and edema; hematuria and abnormal urinary sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and lipiduria. In a specific
1300 embodiment, the present invention provides methods of treating paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition comprising an compound of the present invention with or without concomitent administration of a complement C5 inhibitor or C5 convertase inhibitor such as Soliris.
1305 In a specific embodiment, the present invention provides use 1 -(2-((1 R,3S,5R)-3-
(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1 .0]hexan-2-yl)-2- oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide for reducing the dysfunction of the immune and/or hemostatic systems associated with extracorporeal circulation. 1 -(2- ((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-
1310 azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide can be used in any procedure which involves circulating the patient's blood from a blood vessel of the patient, through a conduit, and back to a blood vessel of the patient, the conduit having a luminal surface comprising a material capable of causing at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte
1315 adhesion. Such procedures include, but are not limited to, all forms of ECC, as well as procedures involving the introduction of an artificial or foreign organ, tissue, or vessel into the blood circuit of a patient. More particularly, such procedures include, but are not limited to, transplantation procedures including kidney, liver, lung or heart transplant procedures and islet cell transplant procedures.
1320 The various crystalline forms of the disclosure may be used alone or in
combination, or formulated with one or more excipients or other active pharmaceutical ingredients to provide formulations suitable for the treatment of the indications identified above.
The following non-limiting examples are illustrative of the disclosure.
1325 EXAMPLES
Form A
To 20mg of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide free base, 500μΙ_ of heptane was added. On stirring at room temperature a suspension
1330 was formed. This suspension was heated to 40°C at 1 °C/min and held for 30 minutes at which point it was cooled at 0.5°C/min to 5°C where it was held for 30 minutes. The resulting solid was collected by vacuum filtration and dried at 40°C under vacuum for 72 hours before analysis. No change from the starting material is seen.
This form was weakly crystalline by XRPD and the DSC trace is characterized by
1335 an endothermic event at ~132°C immediately followed by an exothermic event at ~150°C and a higher temperature endothermic event at ~205°C. This form has 1-2% weight loss on heating. The XRPD for form A is shown in Figure 1. The DSC for form A is shown in Figure 2.
Table 1. Powder X-Ray Diffraction Peaks Modification Form A
Angle d value Intensity
°20 A %
4.72 18.71 25.30
5.88 15.03 26.50
8.40 10.53 34.60
10.41 8.49 33.70
1 1.35 7.80 37.60
12.76 6.94 49.20
14.37 6.16 89.00
14.73 6.01 100.00
16.39 5.41 83.70
18.90 4.70 71 .00
19.20 4.62 77.70
22.99 3.87 43.00
26.83 3.32 42.80
1340
Form B
To 20mg of l-(2-((lR,3S,5R)-3-(((R)-l-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrazolo[3,4-c]pyridine-3-carboxamide free base, 500μί of DCM or THF was added. On stirring at room temperature a suspension was formed.
1345 This suspension was heated to 35°C (DCM) or 40°C (THF) at l°C/min and held for 30 minutes at which point it was cooled at 0.5°C/min to 5°C where it was held for 30 minutes. The experiment with THF remained a suspension at the higher temperatue while the sample in DCM was a clear solution. The resulting solid was collected by vacuum filtration and dried at 40°C under vacuum for 72 hours before analysis.
1350 This form was crystalline by XRPD and the DSC trace is characterized by an endothermic event at ~205°C (ΔΗί 80 J/g). A weight loss of -0.3% is seen on heating through ~150°C. This weight loss is common in all crystalline forms made. The XRPD for Form B is shown in Figure 3. The DSC for Form B is shown in Figure 4.
Table 2. Powder X-Ray Diffraction Peaks Modification Form B
Angle d value Intensity
°2Θ A %
7.37 12.00 100.00
7.84 1 1 .28 1 1 .10
9.18 9.64 24.60
1 1 .06 8.00 26.20
12.21 7.25 1 1 .50
13.04 6.79 20.60
14.59 6.07 12.10
15.41 5.75 83.50
16.13 5.49 20.40
17.07 5.19 21 .40
18.01 4.93 28.70
18.83 4.71 35.70
19.58 4.53 17.30
19.93 4.45 20.80
20.12 4.41 21 .40
20.64 4.30 14.90
20.96 4.24 13.60
21 .36 4.16 13.90
22.07 4.03 13.00
22.60 3.94 24.20
22.99 3.87 24.70
24.46 3.64 35.40
24.83 3.59 25.40
25.25 3.53 17.40
25.85 3.45 23.10
26.61 3.35 16.70
27.07 3.29 19.70
27.54 3.24 25.40
28.33 3.15 18.00
29.53 3.02 15.80
1355 Form C Method 1. To 20mg of l-(2-((lR,3S,5R)-3-(((R)-l-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrazolo[3,4- c]pyridine-3-carboxamide free base, 500μί of EtOAc, EtO Ac/heptane 1 : 1 or MTBE was added.
On stirring at room temperature a suspension was formed. These suspensions were heated to 1360 40°C (THF) at 1 °C/min and held for 30 minutes at which point it was cooled at 0.5°C/min to 5°C where it was held for 30 minutes. The resulting solid was collected by vacuum filtration and dried at 40°C under vacuum for 72 hours before analysis.
Method 2. To lOOmg of Form C, 1250 of EtO Ac or TBME was added. The resulting suspension was stirred for 24 hours at room temperature and the resulting solid was collected by 1365 vacuum filtration and dried at 40°C under vacuum for 72 hours before analysis.
This form was crystalline by XRPD and the DSC trace is characterized by an endothermic event at ~202°C (ΔΗί 86 J/g). A weight loss of -0.3% is seen on heating through ~150°C. This weight loss is common in all crystalline forms made. The XRPD for Form C is shown in Figure
5. The DSC of Form C is shown in Figure 6.
1370 Table 3. Powder X-Ray Diffraction Peaks Modification Form C
Angle d value Intensity
°20 A %
6.93 12.76 100.00
8.83 10.02 54.50
10.58 8.36 15.10
1 1 .56 7.65 36.60
12.98 6.82 29.30
13.56 6.53 14.80
14.04 6.31 36.00
14.60 6.07 61 .30
14.85 5.97 66.30
16.65 5.32 92.20
17.41 5.09 21 .30
17.77 4.99 30.60
18.46 4.81 21 .80
19.54 4.54 51 .10
21 .38 4.16 13.80
22.03 4.04 20.40
22.75 3.91 16.60
24.53 3.63 24.30
25.1 1 3.55 28.80
25.77 3.46 53.00
26.62 3.35 30.20
27.47 3.25 34.70
29.41 3.04 20.20
29.88 2.99 20.60
Form D To 20mg of l-(2-((lR,3S,5R)-3-(((R)-l-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrazolo[3,4-c]pyridine-3-carboxamide free base, 1375 500μί of IPA or ACN was added. On stirring at room temperature a suspension was formed.
These suspensions were heated to 40°C (THF) at l°C/min and held for 30 minutes at which point it was cooled at 0.5°C/min to 5°C where it was held for 30 minutes. The resulting solid was collected by vacuum filtration and dried at 40°C under vacuum for 72 hours before analysis.
This form was crystalline by XRPD and the DSC trace is characterized by a broad
1380 endothermic event starting at ambient temperature followed by an endothermic event at ~ 130°C and a higher temperature endotherm at 205°C. A weight loss of ~2% is seen on heating. The XRPD for Form D is shown in Figure 7. The DSC for Form D is shown in Figure 8.
Table 4. Powder X-Ray Diffraction Peaks Modification Form D
Angle d value Intensity
°20 A %
6.03 14.65 100.00
7.23 12.23 30.60
7.79 1 1 .34 33.50
8.19 10.80 56.20
9.26 9.55 47.40
10.85 8.15 24.90
1 1 .63 7.61 27.50
12.62 7.01 31 .60
12.95 6.84 34.70
13.66 6.48 42.60
14.17 6.25 48.30
14.71 6.02 57.30
15.31 5.79 31 .30
16.14 5.49 42.60
17.15 5.17 60.80
17.55 5.05 52.00
18.33 4.84 100.00
19.16 4.63 53.30
19.69 4.51 47.30
20.27 4.38 26.60
21 .82 4.07 32.00
22.45 3.96 36.50
23.43 3.80 66.00
25.05 3.56 77.70
27.48 3.25 48.30
28.35 3.15 45.30
28.76 3.10 33.80
29.56 3.02 56.00
1385 Form E [hydrate] To 20mg of l-(2-((lR,3S,5R)-3-(((R)-l-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrazolo[3,4-c]pyridine-3-carboxamide free base, 500μί of 10% MeOH in water, 50% EtOH in water or 50% ACN in water was added. On stirring at room temperature a suspension was formed. This suspension was heated to 40°C at l°C/min
1390 and held for 30 minutes at which point it was cooled at 0.5°C/min to 5°C where it was held for 30 minutes. The experiment with 10% MeOH in water remained a suspension at 40°C while the samples in 50% EtOH in water or 50% ACN in water were clear solutions and remained so at 5°C. The resulting solid from 10% MeOH in water was collected by vacuum filtration and dried at 40°C under vacuum for 72 hours before analysis. The solutions in50% EtOH in water or 50%
1395 ACN in water were allowed to evaporate under ambient conditions and powders obtained
collected and analyzed.
This form was crystalline by XRPD and the DSC trace is characterized by a broad endothermic event starting at ambient temperature followed by an endothermic event at ~ 125°C immediately followed by an exothermic event at ~140°C and a higher temperature endotherm at
1400 202°C. A weight loss of -2% is seen on heating. The XRPD for Form E is shown in Figure 9.
The DSC for Form E is shown in Figure 10.
Table 5. Powder X-Ray Diffraction Peaks Modification Form E
Angle d value Intensity
°2Θ A %
4.76 18.56 21 .70
7.67 1 1 .52 24.00
8.56 10.33 22.50
10.45 8.47 43.90
13.24 6.69 28.60
13.89 6.37 29.20
14.63 6.06 64.70
14.96 5.92 100.00
15.53 5.71 42.30
16.13 5.49 56.80
16.51 5.37 41 .40
17.63 5.03 36.40
19.06 4.66 51 .20
21 .95 4.05 37.40
22.43 3.96 41 .30
25.97 3.43 67.80
26.95 3.31 75.30
27.80 3.21 76.50
Form F
1405 To 20mg of l-(2-((lR,3S,5R)-3-(((R)-l-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrazolo[3,4-c]pyridine-3-carboxamide free base, 500μί of nitromethane was added. On stirring at room temperature a suspension was formed. This suspension was heated to 40°C (THF) at l°C/min and held for 30 minutes at which point it was cooled at 0.5°C/min to 5°C where it was held for 30 minutes. The resulting solid was 1410 collected by vacuum filtration and dried at 40°C under vacuum for 72 hours before analysis.
This form was crystalline by XRPD and the DSC trace is characterized by an endothermic event at ~205°C (ΔΗί 82 J/g). A weight loss of -0.3% is seen on heating through ~150°C. This weight loss is common in all crystalline forms made. XRPD for Form F is shown in Figure 1 1.
DSC for Form F is shown in Figure 12.
1415 Table 6. Powder X-Ray Diffraction Peaks Modification Form F
Angle d value Intensity
°2Θ A %
6.91 12.80 14.50
7.99 1 1 .06 100.00
8.85 9.99 17.90
9.64 9.17 21 .50
10.58 8.36 13.00
1 1.80 7.50 12.30
13.60 6.51 29.10
14.74 6.01 40.10
15.15 5.85 23.90
16.77 5.29 55.30
17.46 5.08 29.60
18.07 4.91 26.00
18.64 4.76 19.40
19.07 4.66 28.20
20.45 4.34 19.70
21.52 4.13 21 .90
21.89 4.06 25.80
23.45 3.79 39.30
26.10 3.41 23.20
26.76 3.33 24.30
27.62 3.23 21 .90
27.89 3.20 23.40
1420 X-ray powder diffraction (PXRD) data were obtained using a Bruker GADDS
(General Area Detector Diffraction System) manual chi platform goniometer. Powder samples were placed in thin walled glass capillaries of 1 mm or less in diameter; the capillary was rotated during data collection. The sample-detector distance was 17 cm. The radiation was Cu K ( = 1 .5418 A). Data were collected for 3<2 <35 with a
1425 sample exposure time of at least 300 seconds.
Differential scanning calorimetry was conducted for each crystalline form using a TA Instruments™ model Q1000. For each analysis, the DSC cell/sample chamber was purged with 100 ml/min of ultra-high purity nitrogen gas. The instrument was calibrated with high purity indium. The heating rate was 10 C per minute in the temperature range
1430 between 25 and 300 C. The heat flow, which was normalized by sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram ("W/g"). The plot was made with the endothermic peaks pointing down. The endothermic melt peak (melting point) was evaluated for extrapolated onset temperature.
The TGA instruments used to test the crystalline forms was a TA
1435 Instruments. RTM. High Resolution Thermogravimetric Analyzer Q500 or TA
Instruments. RTM. High Resolution Thermogravimetric Analyzer 2950. Samples of 15 to 20 milligrams were analyzed at a heating rate of 10°C. per minute in the temperature range between 25°C. and about 300°C.
1440

Claims

CLAIMS What is claimed is:
1 . A crystalline form of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-
1445 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide.
2. The crystalline form according to claim 1 comprising 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
1450 pyrazolo[3,4-c]pyridine-3-carboxamide Form A.
3. The crystalline form according to claim 1 or 2 consisting essentially of Form A.
4. The crystalline form according to claims 1-3, wherein said Form A is in substantially 1455 pure form.
5. The crystalline form according to claim 1 -4 characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of 4.72±0.2°, 5.88±0.2°, 8.40±0.2°, 10.41 ±0.2°, 1 1.35±0.2°, 12.76±0.2°, 14.37±0.2°,
1460 14.73±0.2°, 16.39±0.2°, 18.90±0.2°, 19.20±0.2°, 22.99±0.2° and 26.83±0.2°, at a
temperature of about 22°C.
6. The crystalline form according to claim 5 further characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values selected from the group consisting
1465 of 4.72±0.2°, 5.88±0.2°, 8.40±0.2°, 10.41 ±0.2°, 1 1.35±0.2°, 12.76±0.2°, 14.37±0.2°, 14.73±0.2°, 16.39±0.2°, 18.90±0.2°, 19.20±0.2°, 22.99±0.2° and 26.83±0.2°, at a temperature of about 22°C.
7. A crystalline form of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-
1470 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.
8. A crystalline form of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-
1475 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 2.
9. A pharmaceutical composition comprising the crystalline form according to claims 1-10 1480 and a pharmaceutically acceptable carrier or diluent.
10. The pharmaceutical composition according to claim 9 wherein said crystalline form is Form A.
1485 1 1. The pharmaceutical composition according to claim 10 wherein said Form A is in substantially pure form.
12. A combination, in particular a pharmaceutical combination, comprising a
therapeutically effective amount of the crystalline from according to any one of claims 1 -8
1490 and a second therapeutically active agent.
13. The pharmaceutical composition according to claim 12 wherein said crystalline form is Form A.
1495 14. The pharmaceutical composition according to claim 13 wherein said Form A is in substantially pure form.
15. A method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, 1500 comprising administering to the mammal a therapeutically-effective amount of a
crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to claims 1 -8.
1505 16. The method according to claim 15 wherein said crystalline form is Form A.
17. The method according to claim 16 wherein said Form A is in substantially pure form.
18. The method according to claim 15, wherein the subject is a human.
1510
19. A composition comprising at least 90 weight % of the crystalline form according to claims 2-8, based on the weight of the composition.
20. A process of making Form A of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- 1515 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 1.
21. The crystalline form according to claim 1 comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
1520 pyrazolo[3,4-c]pyridine-3-carboxamide Form B.
22. The crystalline form according to claim 1 or 21 consisting essentially of Form B.
23. The crystalline form according to claims 1 or 21-22, wherein said Form B is in 1525 substantially pure form.
24. The crystalline form according to claim 1 and 21-23 characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of 7.37±0.2°, 7.84±0.2°, 9.18±0.2°, 1 1.06±0.2°, 12.21 ±0.2°, 13.04±0.2°, 14.59±0.2°,
1530 15.41 ±0.2°, 16.13±0.2°, 17.07±0.2°, 18.01 ±0.2°, 18.83±0.2°, 19.58±0.2°, 19.93±0.2°, 20.12±0.2°, 20.64±0.2°, 20.96±0.2°, 21 .36±0.2°, 22.07±0.2°, 22.60±0.2°, 22.99±0.2°, 24.46±0.2°, 24.83±0.2°, 25.25±0.2°, 25.85±0.2°, 26.61 ±0.2°, 27.07±0.2°, 27.54±0.2°, 28.33±0.2° and 29.53±0.2°, at a temperature of about 22°C.
1535 25. The crystalline form according to claim 24 further characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values selected from the group consisting of 7.37±0.2°, 7.84±0.2°, 9.18±0.2°, 1 1.06±0.2°, 12.21 ±0.2°, 13.04±0.2°, 14.59±0.2°, 15.41 ±0.2°, 16.13±0.2°, 17.07±0.2°, 18.01 ±0.2°, 18.83±0.2°, 19.58±0.2°, 19.93±0.2°, 20.12±0.2°, 20.64±0.2°, 20.96±0.2°, 21 .36±0.2°, 22.07±0.2°, 22.60±0.2°, 22.99±0.2°,
1540 24.46±0.2°, 24.83±0.2°, 25.25±0.2°, 25.85±0.2°, 26.61 ±0.2°, 27.07±0.2°, 27.54±0.2°, 28.33±0.2° and 29.53±0.2°, at a temperature of about 22°C.
26. A crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
1545 pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 3.
27. A crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
1550 pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 4.
28. A pharmaceutical composition comprising the crystalline form according to claims 1 and 21-27 and a pharmaceutically acceptable carrier or diluent.
1555
29. The pharmaceutical composition according to claim 28 wherein said crystalline form is Form B.
30. The pharmaceutical composition according to claim 29 wherein said Form B is in 1560 substantially pure form.
31. A combination, in particular a pharmaceutical combination, comprising a
therapeutically effective amount of the crystalline from according to any one of claims 1 and 21-27 and a second therapeutically active agent.
1565
32. The pharmaceutical composition according to claim 31 wherein said crystalline form is Form B.
33. The pharmaceutical composition according to claim 32 wherein said Form B is in 1570 substantially pure form.
34. A method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a
1575 crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to claims 1 and 21-27.
35. The method according to claim 34 wherein said crystalline form is Form B.
1580
36. The method according to claim 35 wherein said Form B is in substantially pure form.
37. The method according to claim 34, wherein the subject is a human.
1585 38. A composition comprising at least 90 weight % of the crystalline form according to claims 21 -27, based on the weight of the composition.
39. A process of making Form B of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- 1590 pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 2.
40. The crystalline form according to claim 1 comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide Form C.
1595
41. The crystalline form according to claim 1 or 40 consisting essentially of Form C.
42. The crystalline form according to claims 1 and 40-41 , wherein said Form C is in substantially pure form.
1600
43. The crystalline form according to claim 1 and 40-42 characterized by a x-ray powder diffraction pattern comprising four or more 20 values selected from the group consisting of 6.93±0.2°, 8.83±0.2°, 10.58±0.2°, 1 1 .56±0.2°, 12.98±0.2°, 13.56±0.2°, 14.04±0.2°, 14.60±0.2°, 14.85±0.2°, 16.65±0.2°, 17.41 ±0.2°, 17.77±0.2°, 18.46±0.2°, 19.54±0.2°,
1605 21.38±0.2°, 22.03±0.2°, 22.75±0.2°, 24.53±0.2°, 25.1 1 ±0.2°, 25.77±0.2°, 26.62±0.2°, 27.47±0.2°, 29.41 ±0.2° and 29.88±0.2°, at a temperature of about 22°C.
44. The crystalline form according to claim 43 further characterized by a x-ray powder diffraction pattern comprising five or more 20 values selected from the group consisting
1610 of 6.93±0.2°, 8.83±0.2°, 10.58±0.2°, 1 1 .56±0.2°, 12.98±0.2°, 13.56±0.2°, 14.04±0.2°, 14.60±0.2°, 14.85±0.2°, 16.65±0.2°, 17.41 ±0.2°, 17.77±0.2°, 18.46±0.2°, 19.54±0.2°, 21.38±0.2°, 22.03±0.2°, 22.75±0.2°, 24.53±0.2°, 25.1 1 ±0.2°, 25.77±0.2°, 26.62±0.2°, 27.47±0.2°, 29.41 ±0.2° and 29.88±0.2°, at a temperature of about 22°C.
1615 45. A crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 5.
1620 46. A crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 6.
1625 47. A pharmaceutical composition comprising the crystalline form according to claims 1 and 40-46 and a pharmaceutically acceptable carrier or diluent.
48. The pharmaceutical composition according to claim 47 wherein said crystalline form is Form C.
1630
49. The pharmaceutical composition according to claim 48 wherein said Form C is in substantially pure form.
50. A combination, in particular a pharmaceutical combination, comprising a
1635 therapeutically effective amount of the crystalline from according to any one of claims 1 and 40-46 and a second therapeutically active agent.
51. The pharmaceutical composition according to claim 50 wherein said crystalline form is Form C.
1640
52. The pharmaceutical composition according to claim 51 wherein said Form C is in substantially pure form.
53. A method of treating a disorder or a disease in a subject mediated by complement 1645 activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to claims 1 and 40-46.
1650
54. The method according to claim 53 wherein said crystalline form is Form C.
55. The method according to claim 54 wherein said Form C is in substantially pure form.
1655 56. The method according to claim 53, wherein the subject is a human.
57. A composition comprising at least 90 weight % of the crystalline form according to claims 40-46, based on the weight of the composition.
1660 58. A process of making Form C of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 3.
59. The crystalline form according to claim 1 comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3- 1665 chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide Form D.
60. The crystalline form according to claim 1 and 59 consisting essentially of Form D.
1670 61. The crystalline form according to claims 1 and 59-60, wherein said Form D is in
substantially pure form.
62. The crystalline form according to claim 1 and 59-61 characterized by a x-ray powder diffraction pattern comprising four or more 20 values selected from the group consisting
1675 of 6.03±0.2°, 7.23±0.2°, 7.79±0.2°, 8.19±0.2°, 9.26±0.2°, 10.85±0.2°, 1 1 .63±0.2°,
12.62±0.2°, 12.95±0.2°, 13.66±0.2°, 14.17±0.2°, 14.71 ±0.2°, 15.31 ±0.2°, 16.14±0.2°, 17.15±0.2°, 17.55±0.2°, 18.33±0.2°, 19.16±0.2°, 19.69±0.2°, 20.27±0.2°, 21.82±0.2°, 22.45±0.2°, 23.43±0.2°, 25.05±0.2°, 27.48±0.2°, 28.35±0.2°, 28.76±0.2° and 29.56±0.2°, at a temperature of about 22°C.
1680
63. The crystalline form according to claim 62 further characterized by a x-ray powder diffraction pattern comprising five or more 20 values selected from the group consisting of 6.03±0.2°, 7.23±0.2°, 7.79±0.2°, 8.19±0.2°, 9.26±0.2°, 10.85±0.2°, 1 1 .63±0.2°, 12.62±0.2°, 12.95±0.2°, 13.66±0.2°, 14.17±0.2°, 14.71 ±0.2°, 15.31 ±0.2°, 16.14±0.2°,
1685 17.15±0.2°, 17.55±0.2°, 18.33±0.2°, 19.16±0.2°, 19.69±0.2°, 20.27±0.2°, 21.82±0.2°,
22.45±0.2°, 23.43±0.2°, 25.05±0.2°, 27.48±0.2°, 28.35±0.2°, 28.76±0.2° and 29.56±0.2°, at a temperature of about 22°C.
64. A crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-
1690 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 7.
65. A crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-
1695 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 8.
66. A pharmaceutical composition comprising the crystalline form according to claims 1 1700 and 59-65 and a pharmaceutically acceptable carrier or diluent.
67. The pharmaceutical composition according to claim 66 wherein said crystalline form is Form D.
1705 68. The pharmaceutical composition according to claim 67 wherein said Form D is in substantially pure form.
69. A combination, in particular a pharmaceutical combination, comprising a
therapeutically effective amount of the crystalline from according to any one of claims 1
1710 and 59-65 and a second therapeutically active agent.
70. The pharmaceutical composition according to claim 69 wherein said crystalline form is Form D.
1715 71. The pharmaceutical composition according to claim 70 wherein said Form D is in substantially pure form.
72. A method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, 1720 comprising administering to the mammal a therapeutically-effective amount of a
crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to claims 1 and 59-65.
1725 73. The method according to claim 72 wherein said crystalline form is Form D.
74. The method according to claim 73 wherein said Form D is in substantially pure form.
75. The method according to claim 72, wherein the subject is a human.
1730
76. A composition comprising at least 90 weight % of the crystalline form according to claims 59-65, based on the weight of the composition.
77. A process of making Form D of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-
1735 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 4.
78. The crystalline form according to claim 1 comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
1740 pyrazolo[3,4-c]pyridine-3-carboxamide Form E.
79. The crystalline form according to claim 1 or 78 consisting essentially of Form E.
80. The crystalline form according to claims 1 and 78-79, wherein said Form E is in 1745 substantially pure form.
81. The crystalline form according to claim 1 and 78-80 characterized by a x-ray powder diffraction pattern comprising four or more 20 values selected from the group consisting of 4.76±0.2°, 7.67±0.2°, 8.56±0.2°, 10.45±0.2°, 13.24±0.2°, 13.89±0.2°, 14.63±0.2°,
1750 14.96±0.2°, 15.53±0.2°, 16.13±0.2°, 16.51 ±0.2°, 17.63±0.2°, 19.06±0.2°, 21.95±0.2°, 22.43±0.2°, 25.97±0.2°, 26.95±0.2° and 27.80±0.2°, at a temperature of about 22°C.
82. The crystalline form according to claim 81 further characterized by a x-ray powder diffraction pattern comprising five or more 20 values selected from the group consisting
1755 of 4.76±0.2°, 7.67±0.2°, 8.56±0.2°, 10.45±0.2°, 13.24±0.2°, 13.89±0.2°, 14.63±0.2°, 14.96±0.2°, 15.53±0.2°, 16.13±0.2°, 16.51 ±0.2°, 17.63±0.2°, 19.06±0.2°, 21.95±0.2°, 22.43±0.2°, 25.97±0.2°, 26.95±0.2° and 27.80±0.2°, at a temperature of about 22°C.
83. A crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-
1760 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 9.
84. A crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-
1765 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 10.
85. A pharmaceutical composition comprising the crystalline form according to claims 1 1770 and 78-84 and a pharmaceutically acceptable carrier or diluent.
86. The pharmaceutical composition according to claim 85 wherein said crystalline form is Form E.
1775 87. The pharmaceutical composition according to claim 86 wherein said Form E is in substantially pure form.
88. A combination, in particular a pharmaceutical combination, comprising a
therapeutically effective amount of the crystalline from according to any one of claims 1
1780 and 78-84 and a second therapeutically active agent.
89. The pharmaceutical composition according to claim 88 wherein said crystalline form is Form E.
90. The pharmaceutical composition according to claim 89 wherein said Form E is in 1785 substantially pure form.
91. A method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, comprising administering to the mammal a therapeutically-effective amount of a
1790 crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to claims 1 and 78-84.
92. The method according to claim 91 wherein said crystalline form is Form E.
1795
93. The method according to claim 92 wherein said Form E is in substantially pure form.
94. The method according to claim 91 , wherein the subject is a human.
1800 95. A composition comprising at least 90 weight % of the crystalline form according to claims 78-84, based on the weight of the composition.
96. A process of making Form E of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-
1805 pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 5.
97. The crystalline form according to claim 1 comprising 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3- chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide Form F.
1810
98. The crystalline form according to claim 1 and 97 consisting essentially of Form F.
99. The crystalline form according to claims 1 and 97-98, wherein said Form F is in substantially pure form.
1815 100. The crystalline form according to claim 1 and 97-99 characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of 6.91 ±0.2°, 7.99±0.2°, 8.85±0.2°, 9.64±0.2°, 10.58±0.2°, 1 1.80±0.2°, 13.60±0.2°, 14.74±0.2°, 15.15±0.2°, 16.77±0.2°, 17.46±0.2°, 18.07±0.2°, 18.64±0.2°, 19.07±0.2°, 20.45±0.2°, 21.52±0.2°, 21 .89±0.2°, 23.45±0.2°, 26.10±0.2°, 26.76±0.2°, 27.62±0.2° and
1820 27.89±0.2°, at a temperature of about 22°C.
101 . The crystalline form according to claim 100 further characterized by a x-ray powder diffraction pattern comprising five or more 2Θ values selected from the group consisting of 6.91 ±0.2°, 7.99±0.2°, 8.85±0.2°, 9.64±0.2°, 10.58±0.2°, 1 1.80±0.2°, 13.60±0.2°,
1825 14.74±0.2°, 15.15±0.2°, 16.77±0.2°, 17.46±0.2°, 18.07±0.2°, 18.64±0.2°, 19.07±0.2°,
20.45±0.2°, 21.52±0.2°, 21 .89±0.2°, 23.45±0.2°, 26.10±0.2°, 26.76±0.2°, 27.62±0.2° and 27.89±0.2°, at a temperature of about 22°C.
102. A crystalline form of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-
1830 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1 1 .
103. A crystalline form of 1 -(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2-
1835 fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in FIG. 12.
104. A pharmaceutical composition comprising the crystalline form according to claims 1 1840 and 97-103 and a pharmaceutically acceptable carrier or diluent.
105. The pharmaceutical composition according to claim 104 wherein said crystalline form is Form F.
1845 106. The pharmaceutical composition according to claim 105 wherein said Form F is in substantially pure form.
107. A combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the crystalline from according to any one of claims 1
1850 and 97-103 and a second therapeutically active agent.
108. The pharmaceutical composition according to claim 107 wherein said crystalline form is Form F.
1855 109. The pharmaceutical composition according to claim 108 wherein said Form F is in substantially pure form.
1 10. A method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, 1860 comprising administering to the mammal a therapeutically-effective amount of a
crystalline form of 1-(2-((1 R,3S,5R)-3-(((R)-1 -(3-chloro-2-fluorophenyl)ethyl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide according to claims 1 and 97-103.
1865 1 1 1 . The method according to claim 1 10 wherein said crystalline form is Form F.
1 12. The method according to claim 1 1 1 wherein said Form F is in substantially pure form.
1870 1 13. The method according to claim 1 10, wherein the subject is a human.
1 14. A composition comprising at least 90 weight % of the crystalline form according to claims 97-103, based on the weight of the composition.
1875 1 15. A process of making Form A of 1-(2-((1 R,3S,5R)-3-(((R)-1-(3-chloro-2- fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide comprising the steps of Example 6.
PCT/IB2013/055301 2012-06-29 2013-06-27 CRYSTALLINE FORMS OF 1-(2-((1R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1Hpyrazolo[3,4-c]pyridine-3-carboxamide WO2014002059A1 (en)

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