WO2014002059A1 - Formes cristallines de 1-(2-((1r,3s,5r)-3-(((r)-1-(3-chloro-2- fluorophényl)éthyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoéthyl)-1h-pyrazolo[3,4-c]pyridine-3-carboxamide - Google Patents

Formes cristallines de 1-(2-((1r,3s,5r)-3-(((r)-1-(3-chloro-2- fluorophényl)éthyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoéthyl)-1h-pyrazolo[3,4-c]pyridine-3-carboxamide Download PDF

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Publication number
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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English (en)
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/fr

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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

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Abstract

L'invention porte sur des formes cristallines du 1-(2-((1R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophényl)éthyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoéthyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Le 1-(2-((1R,3S,5R)-3-(((R)-1-(3-chloro-2-fluorophényl)éthyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoéthyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide est utile dans le traitement chez un sujet d'un trouble ou d'une maladie à médiation par l'activation du complément, en particulier à médiation par l'activation de la voie alternative d'activation du complément.
PCT/IB2013/055301 2012-06-29 2013-06-27 Formes cristallines de 1-(2-((1r,3s,5r)-3-(((r)-1-(3-chloro-2- fluorophényl)éthyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoéthyl)-1h-pyrazolo[3,4-c]pyridine-3-carboxamide WO2014002059A1 (fr)

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