Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• This invention provides advantageous isolated morphic forms of the Complement factor D inhibitors Compound 1 and Compound 2.
• the complement system is a part of the innate immune system which does not adapt to changes over the course of the host’s life, but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens.
• This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction.
• Over thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells), and agglutination (clustering and binding of pathogens together).
• Complement Factor D plays an early and central role in activation of the alternative pathway of the complement cascade. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of a thioester bond within the C3 protein to produce C3(H20), which associates with Factor B to form the 03(I3 ⁇ 40)B complex. Complement Factor D acts to cleave Factor B within the C3(H20)B complex to form Ba and Bb. The Bb fragment remains associated with C3(H20) to form the alternative pathway C3 convertase C3(H20)Bb.
• C3b generated by any of the C3 convertases also associates with Factor B to form C3bB, which Factor D cleaves to generate the later stage alternative pathway C3 convertase C3bBb.
• This latter form of the alternative pathway C3 convertase may provide important downstream amplification within all three of the defined complement pathways, leading ultimately to the recruitment and assembly of additional factors in the complement cascade pathway, including the cleavage of C5 to C5a and C5b.
• C5b acts in the assembly of factors C6, C7, C8, and C9 into the membrane attack complex, which can destroy pathogenic cells by lysing the cell.
• complement The dysfunction of or excessive activation of complement has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.
• activation of the alternative pathway of the complement cascade contributes to the production of C3a and C5a, both potent anaphylatoxins, which also have roles in a number of inflammatory disorders. Therefore, in some instances, it is desirable to decrease the response of the complement pathway, including the alternative complement pathway.
• disorders mediated by the complement pathway include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis.
• AMD age-related macular degeneration
• PNH paroxysmal nocturnal hemoglobinuria
• multiple sclerosis multiple sclerosis
• rheumatoid arthritis Some examples include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and
• ASD Age-related macular degeneration
• Paroxysmal nocturnal hemoglobinuria is a non-malignant, hematological disorder characterized by the expansion of hematopoietic stem cells and progeny mature blood cells that are deficient in some surface proteins. PNH erythrocytes are not capable of modulating their surface complement activation, which leads to the typical hallmark of PNH - the chronic activation of complement mediated intravascular anemia.
• the anti- C5 monoclonal antibody eculizumab has been approved in the U.S. for treatment of PNH.
• many of the patients treated with eculizumab remain anemic, and many patients continue to require blood transfusions.
• treatment with eculizumab requires life-long intravenous injections.
• C3G is a recently defined entity comprised of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) which encompasses a population of chronic kidney diseases wherein elevated activity of the alternative complement pathway and terminal complement pathway results in glomerular deposits made solely of complement C3 and no immunoglobulin (Ig).
• DDD dense deposit disease
• C3GN C3 glomerulonephritis
• Immune-complex membranoproliferative glomerulonephritis is a renal disease which shares many clinical, pathologic, genetic and laboratory features with C3G, and therefore can be considered a sister disease of C3G.
• an underlying disease or disorder most commonly infections, autoimmune diseases, or monoclonal gammopathies— are identified to which the renal disease is secondary.
• Patients with idiopathic IC-MPGN can have low C3 and normal C4 levels, similar to those observed in C3G, as well as many of the same genetic or acquired factors that are associated with abnormal alternative pathway activity.
• aHUS hemolytic uremic syndrome
• HUS hemolytic uremic syndrome
• NMO neuromyelitis optica
• MG myasthenia gravis
• MG myasthenia gravis
• fatty liver nonalcoholic steatohepatitis
• NASH nonalcoholic steatohepatitis
• Factor D is an attractive target for inhibition or regulation of the complement cascade due to its early and essential role in the alternative complement pathway, and for its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of Factor D effectively interrupts the pathway and attenuates the formation of the membrane attack complex.
• Novartis PCT patent publication W02012/093101 titled“Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration” describes certain Factor D inhibitors. Additional Factor D inhibitors are described in Novartis PCT patent publications W02012093101, WO2013/164802, WO2013/192345, WO2014/002051, WO2014/002052, W02014/002053, WG2014/002054, WO2014/002057, WO2014/002058, WG2014/002059, W02014/005150, WO2014/009833, WO2014/143638, WO2015/009616, WO2015/009977,
• WO2017/035349 WO 2017/035351; WO 2017/035352; WO 2017/035353; WO 2017/035355; WO2017/035357; W02017/035360; WO2017/035361; WO2017//035362; WO2017/035415; WO2017/035401 ; WO2017/035405; WO2017/035413; WO2017/035409; WO2017/035411; WO2017/035417; W02017/035408 WO2015/130784; WO2015/130795; W02015/130806; W02015/130830; WO2015/130838; WO2015/130842; WO2015/130845; and WO2015/130854; and U.S.
• Compound 1 and Compound 2 can be prepared in highly purified morphic forms that exhibit unexpected advantageous therapeutic properties.
• Compound 1 is disclosed in PCT Application WO2015130795 assigned to Achillion Pharmaceuticals and Compound 2 is disclosed in PCT Application WO2017035353 assigned to Achillion Pharmaceuticals.
• the morphic form of Compound 1 is referred to as Form P and the morphic form of Compound 2 is referred to as Form I. These morphic forms are beneficial for therapeutic efficacy and for the manufacture of pharmaceutical formulations.
• Form II of Compound 1 is an unexpected, highly stable, highly crystalline form of solid Compound 1.
• a crystallization study involving 38 unique solvent systems, suspension- and solution-based crystallization modes, and temperatures ranging between 5 and 40 °C was conducted. The study produced a superior crystalline form, Form P, which was identified in five experiments.
• Form P is crystalline by PLM ( Figure 4D) and PXRD ( Figure 4C) and contains 2.7% bound water ( ⁇ 0.9eq.) that is released with a broad endotherm in the DSC from 40-125°C. A final melting endotherm was observed at 155.3°C ( Figure 4B). Heating Form II past the dehydration endotherm and returning to room temperature does not change the crystal-form by PXRD or water content by TGA, indicating that it is a reversible hydrate.
• Form IP hydrate
• Form IV hydrate
• Form V hydrate
• Form VI mixed solvate/hydrate
• Form VII mixed solvate/hydrate
• Form I of Compound 2 is also an unexpected, highly stable, highly crystalline form. As discussed in Example 8 and shown in Figure 13, the XRPD of Compound 2 Form I exhibits a highly crystalline form. As discussed in Example 7, a study was designed to probe the solid behavior of Compound 2. A wide variety of solvents and solvent systems were used resulting in the discovery of Form I.
• Form II of Compound 1 and Form I of Compound 2 have advantageous properties for use as active pharmaceutical ingredients in a solid dosage form and may have increased efficacy in such a formulation.
• Form P of Compound 1 is produced by recrystallization from heptane and isopropyl alcohol, as described in more detail below.
• Form II of Compound 1 is characterized by a PXRD pattern substantially similar to that set forth in FIG. 4C.
• isolated Compound 1 Form P is characterized as having about a 2-3%, for example, a 2.7% weight loss between 40 and 125°C in a differential scanning calorimetry analysis.
• Form I of Compound 2 is produced by recrystallization from heptane and isopropanol, as described in more detail below.
• Form I of Compound 2 is characterized by a XRPD pattern substantially similar to that set forth in Figure 13.
• isolated Compound 1 Form P is characterized as having an exothermic feature at approximately 118 °C and an endotherm onset at approximately 242 °C.
• the present invention generally provides an isolated morphic Form P of Compound
• compositions containing such morphic form methods of inhibiting or reducing the activity of factor D in a host using said isolated morphic form, treating a host having a paroxysmal nocturnal hemoglobinuria or C3 glomerulopathy using the morphic form described herein, and methods of preparing such morphic form.
• the present invention also generally provides an isolated morphic Form I of Compound
• compositions containing such morphic form methods of inhibiting or reducing the activity of factor D in a host using said isolated morphic form, treating a host having a paroxysmal nocturnal hemoglobinuria (PNH) or C3 glomerulopathy (C3G) using the morphic form described herein, and methods of preparing such morphic form.
• PNH paroxysmal nocturnal hemoglobinuria
• C3G C3 glomerulopathy
• a pharmaceutical composition comprising isolated Compound 1 morphic Form P and a pharmaceutically acceptable excipient. In one embodiment a pharmaceutical composition is provided comprising isolated Compound 2 morphic Form I and a pharmaceutically acceptable excipient.
• a method for treating a disorder mediated by Complement factor D comprising administering to a host in need thereof a therapeutically effective amount of isolated Form II of Compound 1.
• PNH paroxysmal nocturnal hemoglobinuria
• C3G C3 glomerulopathy
• a method for treating a disorder selected from membranoproliferative glomerulonephritis type P (MPGNII), nonalcoholic steatohepatitis (NASH), fatty liver, liver inflammation, cirrhosis, or liver failure, dermatomyositis, and amyotrophic lateral sclerosis comprising administering to a host in need thereof a therapeutically effective amount of isolated Form II of Compound 1.
• a method for treating a disorder selected from multiple sclerosis, arthritis, respiratoiy disease, cardiovascular disease, COPD, rheumatoid arthritis, atypical hemolytic uremic syndrome, and typical hemolytic uremic syndrome comprising administering to a host in need thereof a therapeutically effective amount of isolated Form II of Compound 1.
• a method for treating a disorder selected from membrane glomerulonephritis, age-related macular degeneration (AMD), retinal degeneration, and type I diabetes or complications thereof comprising administering to a host in need thereof a therapeutically effective amount of isolated Form P of Compound 1.
• a method for treating a disorder mediated by Complement factor D comprising administering to a host in need thereof a therapeutically effective amount of isolated Form I of Compound 2.
• PNH paroxysmal nocturnal hemoglobinuria
• C3G C3 glomerulopathy
• a method for treating a disorder selected from membranoproliferative glomerulonephritis type P (MPGNII), nonalcoholic steatohepatitis (NASH), fatty liver, liver inflammation, cirrhosis, or liver failure, dermatomyositis, and amyotrophic lateral sclerosis comprising administering to a host in need thereof a therapeutically effective amount of isolated Form I of Compound 2.
• a method for treating a disorder selected from multiple sclerosis, arthritis, respiratoiy disease, cardiovascular disease, COPD, rheumatoid arthritis, atypical hemolytic uremic syndrome, and typical hemolytic uremic syndrome comprising administering to a host in need thereof a therapeutically effective amount of isolated Form I of Compound 2.
• a method for treating a disorder selected from membrane glomerulonephritis, age-related macular degeneration (AMD), retinal degeneration, and type I diabetes or complications thereof comprising administering to a host in need thereof a therapeutically effective amount of isolated Form I of Compound 2.
• a therapeutic method is provided to treat a patient with a complement factor D mediated disorder comprising administering an effective amount of Compound 1 Form II and a C5 inhibitor to the patient in need thereof.
• Compound 1 Form P and the C5 inhibitor have an overlapping therapeutic effect.
• a therapeutic method is provided to treat a patient with a complement factor D mediated disorder comprising administering an effective amount of Compound 1 Form II and eculizumab to the patient in need thereof.
• Compound 1 Form P and eculizumab have an overlapping therapeutic effect.
• a therapeutic method is provided to treat a patient with a complement factor D mediated disorder comprising administering Compound 1 Form P and ravulizumab to the patient in need thereof.
• Compound 1 Form II and ravulizumab have an overlapping therapeutic effect.
• the therapeutic effect can be combinatorial or synergistic inhibition.
• the AUC for Compound 1 Form II and the C5 inhibitor overlap.
• the C5 inhibitor is eculizumab. In one embodiment, the C5 inhibitor is ravulizumab. In one embodiment the C5 inhibitor is a small molecule. In another embodiment the C5 inhibitor is a polyclonal antibody targeting C5. In yet another embodiment the C5 inhibitor is an aptamer.
• a therapeutic method is provided to treat a patient with a complement factor D mediated disorder comprising administering an effective amount of Compound 2 Form I and a C5 inhibitor to the patient in need thereof.
• Compound 2 Form I and the C5 inhibitor have an overlapping therapeutic effect.
• a therapeutic method is provided to treat a patient with a complement factor D mediated disorder comprising administering an effective amount of Compound 2 Form I and eculizumab to the patient in need thereof.
• Compound 2 Form I and eculizumab have an overlapping therapeutic effect.
• a therapeutic method is provided to treat a patient with a complement factor D mediated disorder comprising administering Compound 2 Form I and ravulizumab to the patient in need thereof.
• Compound 2 Form I and ravulizumab have an overlapping therapeutic effect.
• the therapeutic effect can be combinatorial or synergistic inhibition.
• the AUC for Compound 2 Form I and the C5 inhibitor overlap.
• the C5 inhibitor is eculizumab. In one embodiment, the C5 inhibitor is ravulizumab. In one embodiment the C5 inhibitor is a small molecule. In another embodiment the C5 inhibitor is a polyclonal antibody targeting C5. In yet another embodiment the C5 inhibitor is an aptamer.
• FIG. 1 A is a 1 HNMR of amorphous Compound 1, the material used in the solubility studies of Example 2 and the crystallization studies of Example 3.
• the x-axis is the Raman shift measured in cm "1 and the y-axis is intensity measured in counts.
• FIG. IB is a DSC and a TGA graph of amorphous Compound 1, the material used in the solubility studies of Example 2 and the crystallization studies of Example 3.
• the x-axis is temperature measured in °C
• the left y-axis is heat flow measured in (W/g)
• the right y-axis is weight measured in percent.
• FIG. 1C is a PXRD (powder X-ray diffraction) of amorphous Compound 1, the material used in the solubility studies of Example 2 and the crystallization studies of Example 3.
• the x- axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.
• FIG. ID is a PLM image of amorphous Compound 1, the material used in the solubility studies of Example 2 and the crystallization studies of Example 3.
• FIG. IE is a DVS isotherm plot of amorphous Compound 1, the material used in the solubility studies of Example 2 and the crystallization studies of Example 3.
• the x-axis is target P/Po measured in percent and the y-axis is change in mass measured in percent.
• FIG. IF is a modulated DSC graph of amoiphous Compound 1, the material used in the solubility studies of Example 2 and the crystallization studies of Example 3.
• the x-axis is temperature measured in °C
• the left y-axis is heat flow measured in W/g
• the right y-axis is rev. heat flow measured in W/g.
• FIG. 2 is an overlay of PXRD patterns of Form A, Form P, Form PI, Form IV, Form V, Form VI, and Form VII of Compound 1 as discussed in Example 4.
• FIG. 3A is a 1 HNMR of Compound 1 Form A as discussed in Example 4. The x-axis is the Raman shift measured in cm '1 and the y-axis is intensity measured in counts.
• FIG. 3B is a DSC and a TGA graph of Compound 1 Form A as discussed in Example 4.
• the x-axis is temperature measured in °C
• the left y-axis is heat flow measured in (W/g)
• the right y-axi s is weight measured in percent.
• FIG. 3C is a PXRD (powder X-ray diffraction) of Compound 1 Form A as discussed in Example 4.
• the x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.
• FIG. 3D is a PLM image of Compound 1 Form A as discussed in Example 4.
• FIG. 4A is a 1 HNMR of Compound 1 Form P as discussed in Example 4.
• the x-axis is the Raman shift measured in cm '1 and the y-axis is intensity measured in counts.
• FIG. 4B is a DSC and a TGA graph of Compound 1 Form P as discussed in Example 4.
• the x-axis is temperature measured in °C
• the left y-axis is heat flow measured in (W/g)
• the right y-axis is weight measured in percent.
• FIG. 4C is a PXRD (powder X-ray diffraction) of Compound 1 Form II as discussed in Example 4.
• the x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.
• FIG. 4D is a PLM image of Compound 1 Form P as discussed in Example 4.
• FIG. 4E is a DVS isotherm plot of Compound 1 Form P as discussed in Example 4.
• the x-axis is target P/P 0 measured in percent and the y-axis is change in mass measured in percent.
• FIG. 5 is an overlay of PXRD patterns comparing Compound 1 Form III obtained from the crystallization of Compound 1 Form P (discussed in Example 4) and Compound 1 Form PI observed during the relative stability experiments of Example 5.
• the x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.
• FIG. 6A is a PXRD (powder X-ray diffraction) of Compound 1 Form PI as discussed in Example 4.
• the x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.
• FIG. 6B is a DSC and a TGA graph of Compound 1 Form III as discussed in Example 4.
• the x-axis is temperature measured in °C
• the left y-axis is heat flow measured in (W/g)
• the right y-axis is weight measured in percent.
• FIG. 7A is a PXRD (powder X-ray diffraction) of Compound 1 Form IV as discussed in Example 4.
• the x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.
• FIG. 7B is a DSC and a TGA graph of Compound 1 Form IV as discussed in Example 4.
• the x-axis is temperature measured in °C
• the left y-axis is heat flow measured in (W/g)
• the right y-axis is weight measured in percent.
• FIG. 8A is a PXRD (powder X-ray diffraction) of Compound 1 Form V as discussed in Example 4.
• the x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.
• FIG. 8B is a DSC and a TGA graph of Compound 1 Form V as discussed in Example 4.
• the x-axis is temperature measured in °C
• the left y-axis is heat flow measured in (W/g)
• the right y-axis is weight measured in percent.
• FIG. 9A is a PXRD (powder X-ray diffraction) of Compound 1 Form VI as discussed in Example 4.
• the x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.
• FIG. 9B is a DSC and a TGA graph of Compound 1 Form VI as discussed in Example 4.
• the x-axis is temperature measured in °C
• the left y-axis is heat flow measured in (W/g)
• the right y-axis is weight measured in percent.
• FIG. 10A is an overlay of PXRD patterns comparing Compound 1 Form V and
• FIG. 10B is an overlay of PXRD patterns comparing Form Compound 1 V and
• FIG. 11 A is a PXRD (powder X-ray diffraction) of Compound 1 Form VII as discussed in Example 4.
• the x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.
• FIG. 1 IB is a TGA-IRA trace of Compound 1 Form VO as discussed in Example 4.
• the x-axis is temperature measured in °C and the y-axis is weight measured in percent.
• FIG. 12 is an overlay of PXRD patterns comparing Compound 1 Form VI and Compound 1 Form VII as discussed in Example 4. The two PXRD patterns share significant overlap indicating that Compound 1 Form VII is likely a mixed solvate containing water and IPA.
• FIG. 13 is XRPD (X-ray powder diffraction) of Compound 2 Form I as discussed in Example 8.
• the x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.
• FIG. 14 is a DSC and a TGA graph of Compound 2 Form I as discussed in Example 8.
• the x-axis is temperature measured in °C
• the left y-axis is heat flow measured in (W/g)
• the right y-axis is weight measured in percent.
• FIG. 15A is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken as heating was initiated (26 °C).
• FIG. 15B is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 116.4 °C. A slight increase in birefnngent character was detected.
• FIG. 15C is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 188.1 °C. The birefringent character of the sample continues to change at this temperature and fogging of the coverslip was observed.
• FIG. 15D is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 191.6 °C. The fogging of the coverslip was continued to be observed.
• FIG. 15E is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken between 191.6 °C and 236.4 °C.
• FIG. 15F is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 236.4 °C.
• FIG. 15G is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 250.9 °C and the onset of melting was observed.
• FIG. 15H is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 260 °C and melting was observed.
• FIG. 151 is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 262.9 °C and melting was observed.
• FIG. 15J is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 263.4 °C at which point the melting was complete. The heat was turned off.
• FIG. 15K is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 30 °C and no signs of recrystallization were observed.
• FIG. 15L is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 25.7 °C at which point the sample was subjected to reheating.
• FIG. 15M is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 99.3 °C at which point no change to the sample was observed.
• FIG. 15N is an image collected from the hot stage microscopy analysis of Compound 2 Form I as discussed in Example 8. The image was taken at 123.4 °C at which point no change to the sample was observed.
• FIG. 16 is Factor D inhibitors Compound 1 and Compound 2. DETAILED DESCRIPTION OF THE INVENTION
• the drug ritonavir is active in one polymorphic form and inactive in another form, and the inactive form is the more stable.
• Solid forms of compounds can be characterized by analytical methods such as X-ray powder diffraction pattern (XRDP or PXRD), thermogravimetric analysis (TGA), TGA with IR off-gas analysis, differential Scanning Calorimetry (DSC), melting point, FT-Raman spectroscopy, dynamic Vapor Sorption (DVS), polarized light microscopy (PLM) or other techniques known in the art.
• analytical methods such as X-ray powder diffraction pattern (XRDP or PXRD), thermogravimetric analysis (TGA), TGA with IR off-gas analysis, differential Scanning Calorimetry (DSC), melting point, FT-Raman spectroscopy, dynamic Vapor Sorption (DVS), polarized light microscopy (PLM) or other techniques known in the art.
• XRDP or PXRD thermogravimetric analysis
• DSC differential Scanning Calorimetry
• melting point melting point
• FT-Raman spectroscopy FT-
• Isolated morphic Form P of Compound 1 is provided in this invention.
• Compound 1 Form P is characterized by a PXRD pattern in or substantially similar to that set forth in FIG. 4C. In one embodiment, Compound 1 Form P is characterized by a PXRD pattern comprising
• a) 2Q values including at least or selected from 5.1, 7.8, 13.5, 14.0, 15.4, 15.6, 18.6,
• PXRD powder X-ray diffraction
• the isolated crystalline Form P of claim 1, wherein the PXRD pattern comprises at least four 2theta values selected from 5.1+0.2°, 7.8+0.2°, 13.5+0.2°, 14.0+0.2°, 15.4+0.2°, 15.6+0.2°, 18.6+0.2°, 20.5+0.2°, 20.7+0.2°, and 23.4+0.2° is provided.
• Compound 1 Form P is characterized by a PXRD pattern comprising a) 2Q values including at least or selected from 5.1, 7.8, 13.5, 14.0, 15.4, 15.6, 18.6,
• 2Q values including at least or selected from 5.1, 7.8, 13.5, 14.0, 15.4, 15.6, 18.6, 20.5, 20.7, and 23.4 +/- 0.2 °20 includes the following 2Q values 5.1 +/- 0.2, 7.8 +/- 0.2, 13.5 +/- 0.2, 14.0 +/- 0.2, 15.4 +/- 0.2, 15.6 +/- 0.2, 18.6 +/- 0.2, 20.5 +/- 0.2, 20.7 +/- 0.2, and 23.4 +/- 0.2.
• isolated Compound 1 Form P is characterized as having approximately a 2-3%, for example, a 2.7% weight loss between 40 and 125°C in a differential scanning calorimetry analysis.
• Compound 1 Form P can be prepared using selective crystallization.
• the method can be carried out by treating a solution comprising a suitable solvents) and Compound 1 optionally in the presence of one or more seeds comprising Compound 1 Form P with conditions that provide for the ciystallization of Compound 1 Form P.
• the selective crystallization can be carried out in any suitable organic solvent. For example, it can be carried out in an aprotic solvent or a mixture thereof.
• the selective crystallization can be carried out at, for example, by cycling the temperature between 40°C and 5°C. In one embodiment, the crystallization is conducted while cycling the temperature in a solvent system of heptane:THF.
• the crystallization is conducted while cycling the temperature in a solvent system of heptane:methanol:ethanol. In one embodiment, the crystallization is conducted while cycling the temperature in a solvent system of t-BuOH:l,4 dioxane:ethanol:heptane. In one embodiment, the ciystallization is conducted while cycling the temperature in a solvent system of cyclohexane:toluene:acetonitrile.
• Compound 1 Form P is produced by recrystallization in a solution of isopropyl alcohol and heptane.
• Isolated morphic Form IP of Compound 1 is provided in this invention.
• Compound 1 Form PI is characterized by a PXRD pattern in or substantially similar to that set forth in FIG. 6A.
• Compound 1 Form IP is characterized by a PXRD pattern comprising
• Compound 1 Form IP is characterized by a PXRD pattern composing
• isolated Compound 1 Form III is characterized as having a 4.0% weight loss between 40 and 125°C in a differential scanning calorimetry analysis.
• Compound 1 Form III can be prepared using selective crystallization.
• the method can be carried out by treating a solution comprising a suitable solvents) and Compound 1 optionally in the presence of one or more seeds comprising Compound 1 Form IP with conditions that provide for the crystallization of Compound 1 Form PI.
• the selective crystallization can be carried out in any suitable organic solvent. For example, it can be carried out in an aprotic solvent or a mixture thereof.
• the selective crystallization can be carried out at, for example, by cycling the temperature between 40°C and 5°C. In one embodiment, the crystallization is conducted in a solvent system of heptane and ethanol while cycling the temperature between 40 °C and 5 °C.
• Isolated morphic Form V of Compound 1 is provided in this invention.
• Compound 1 Form V is characterized by a PXRD pattern in or substantially similar to that set forth in FIG. 8A. In one embodiment, Compound 1 Form V is characterized by a PXRD pattern comprising
• Compound 1 Form V is characterized by a PXRD pattern comprising a) 2Q values including or selected from 5.4, 9.4, 10.0, 15.6, 18.8, 20.3, 20.8, 22.7,
• isolated Compound 1 Form V is characterized as having a broad endotherm at 62.3 °C in a differential scanning calorimetry analysis.
• Compound 1 Form V can be prepared using selective crystallization. The method can be carried out by treating a solution comprising a suitable solvents) and Compound 1 optionally in the presence of one or more seeds comprising Compound 1 Form V with conditions that provide for the crystallization of Compound 1 Form V.
• the selective crystallization can be carried out in any suitable organic solvent. For example, it can be carried out in an aprotic solvent or a mixture thereof.
• the selective crystallization can be carried out at, for example, by cycling the temperature between 40°C and 5°C. In one embodiment, the crystallization is conducted in a solvent system of methanol and 10% (vol) water at approximately 25 °C.
• Compound 2 is conducted in a solvent system of methanol and 10% (vol) water at approximately 25 °C.
• Form I is characterized by a XRPD pattern in or substantially similar to that set forth in Figure 13.
• Compound 2 Form I is characterized by a XRPD pattern comprising
• isolated Compound 2 Form I is characterized as having a weak exothermic feature at approximately 118 °C and a sharp endotherm with an onset of approximately 242 °C in a differential scanning calorimetry analysis. In one embodiment, isolated Compound 2 Form I is characterized as melting between 251 °C and 263 °C during hot stage microscopy.
• Form I can be prepared using selective crystallization.
• the method can be carried out by treating a solution comprising a suitable solvents) and Compound 2 optionally in the presence of one or more seeds comprising Form I to conditions that provide for the crystallization of Form I.
• the selective crystallization can be carried out in any organic suitable solvent. For example, it can be carried out in an aprotic solvent or a mixture thereof.
• the selective crystallization can be carried out at, for example, by cycling the temperature between 40°C and 5°C.
• the present invention includes at least the following embodiments of Compound 2 Form I:
• p) a method of the treatment of a Complement Factor D mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of the isolated crystalline Form I of Compound 2 or a pharmaceutical composition thereof according to any one of embodiments (a)-(n), optionally in a pharmaceutically acceptable excipient for solid dosage delivery;
• “Deuteration” and“deuterated” means that a hydrogen is replaced by a deuterium such that the deuterium exists over natural abundance and is thus“enriched”.
• An enrichment of 50% means that rather than hydrogen at the specified position the deuterium content is 50%.
• the term“enriched” as used herein does not mean percentage enriched over natural abundance.
• the enrichment of deuterium in the specified position of the compound described herein is at least 90%.
• A“dosage form” means a unit of administration of an active agent.
• dosage forms include tablets, capsules, gel caps, injections, suspensions, liquids, intravenous fluids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.
• “Pharmaceutical compositions” are compositions comprising at least one active agent, such as a compound or salt of one of the active compounds disclosed herein, and at least one other substance, such as a carrier. Pharmaceutical compositions optionally contain more than one active agent. “Pharmaceutical combinations” or“combination therapy” refers to the administration of at least two active agents, and in one embodiment, three or four or more active agents which may be combined in a single dosage form or provided together in separate dosage forms optionally with instructions that the active agents are to be used together to treat a disorder.
• carrier means a diluent, excipient, or vehicle with which a morphic form is provided.
• A“pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, is sufficiently non-toxic, and neither biologically nor otherwise undesirable.
• A“pharmaceutically acceptable excipient” as used in the present application includes both one and more than one such excipient.
• A“patient” or“host” is a human or non-human animal, including, but not limited to, simian, avian, feline, canine, bovine, equine or porcine in need of medical treatment.
• Medical treatment can include treatment of an existing condition, such as a disease or disorder, or a prophylactic or diagnostic treatment.
• the patient or host is a human patient.
• the patient such as a host is treated to prevent a disorder or disease described herein.
• isolated refers to the material in substantially pure form.
• An isolated compound does not have another component that materially affects the properties of the compound.
• an isolated form is at least 60, 70, 80, 90, 95, 98 or 99% pure.
• the isolated morphic forms described herein can be administered in an effective amount to a host to treat any of the disorders described herein using any suitable approach which achieves the desired therapeutic result.
• the amount and timing of the isolated morphic forms administered will, of course, be dependent on the host being treated, the instructions of the supervising medical specialist, on the time course of the exposure, on the manner of administration, on the pharmacokinetic properties of the particular active compound, and on the judgment of the prescribing physician.
• the dosages given below are a guideline and the physician can titrate doses of the compound to achieve the treatment that the physician considers appropriate for the host.
• the physician can balance a variety of factors such as age and weight of the host, presence of preexisting disease, as well as presence of other diseases.
• an effective amount of a morphic form as described herein, or the morphic form described herein in combination or alternation with, or preceded by, concomitant with or followed by another active agent can be used in an amount sufficient to (a) inhibit the progression of a disorder mediated by the complement pathway, including an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder; (b) cause a regression of an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder; (c) cause a cure of an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder; or inhibit or prevent the development of an inflammatory, immune, including an autoimmune, disorder or complement Factor D related disorder. Accordingly, an effective amount of the morphic form or composition described herein will provide a sufficient amount of the active agent when administered to a patient to provide a clinical benefit.
• the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., a pill, a capsule, a tablet, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation.
• Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
• the therapeutically effective dosage of the morphic forms described herein will be determined by the health care practitioner depending on the condition, size and age of the patient as well as the route of delivery.
• the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
• Examples are dosage forms with at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500, or 1600 mg of active compound.
• the dosage form has at least about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, lOOOmg, 1200 mg, or 1600 mg of active compound.
• the dosage form can be administered, for example, once a day (q.d.), twice a day (b.i.d.), three times a day (ti.d.), four times a day (q.i.d.), once every other day (Q2d), once every third day (Q3d), as needed, or any dosage schedule that provides treatment of a disorder described herein.
• the isolated morphic forms disclosed herein or used as described herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, intramuscular, inhalation, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
• an oral dosage form for administration can be in any desired form in which the morphic form is stable as a solid.
• the isolated morphic form is delivered in a solid microparticle or nanoparticle.
• the isolated morphic form may be in the form of a plurality of solid particles or droplets having any desired particle size, and for example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more microns, and optionally from about 1 to about 2 microns.
• the isolated morphic forms as disclosed in the present invention have good pharmacokinetic and pharmacodynamics properties, for instance when administered by the oral routes.
• the pharmaceutical formulations can comprise the isolated morphic forms described herein, in any pharmaceutically acceptable carrier.
• a morphic form as described herein is used to create a spray dried dispersion (SDD) that is administered to a patient in need thereof.
• a morphic form is dissolved in an organic solvent such as acetone, methylene chloride, or other organic solvent.
• the solution is pumped through a micronizing nozzle driven by a flow of compressed gas, and the resulting aerosol is suspended in a heated cyclone of air, allowing the solvent to evaporate from the micro droplets, forming particles. Microparticles and nanoparticles can be obtained using this method.
• a morphic form as described herein is administered to a patient in need thereof as a spray dried dispersion (SDD).
• the present invention provides a spray dried dispersion (SDD) comprising a morphic form of the present invention and one or more pharmaceutically acceptable excipients as defined herein.
• SDD comprises a morphic form of the present invention and an additional therapeutic agent.
• SDD comprises a morphic form of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients.
• any of the described spray dried dispersions can be coated to form a coated tablet.
• the spray dried dispersion is formulated into a tablet but is uncoated.
• Particles can be formed from the morphic form as described herein using a phase inversion method.
• tins method the morphic form is dissolved in a suitable solvent, and the solution is poured into a strong non-solvent for the compound to spontaneously produce, under favorable conditions, microparticles or nanoparticles fire method can be used to produce nanoparticles in a wide range of sizes, including, for example, from nanoparticles to microparticles, typically possessing a narrow particle size distribution.
• the morphic form is subjected to a milling process, included but not limited to, hand-milling, rotor-milling, ball -milling, and jet-milling to obtain microparticles and nanoparticles.
• a milling process included but not limited to, hand-milling, rotor-milling, ball -milling, and jet-milling to obtain microparticles and nanoparticles.
• the particle is between about 0.1 nm to about 10000 nm, between about 1 nm to about 1000 nm, between about 10 nm and 1000 nm, between about 1 and 100 nm, between about 1 and 10 nm, between about 1 and 50 nm, between about 100 nm and 800 nm, between about 400 nm and 600 nm, or about 500 nm.
• the micro-particles are no more than about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm, 10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm.
• Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
• the carrier can be inert or it can possess pharmaceutical benefits of its own.
• the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
• Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.
• Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
• Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils.
• Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
• the pharmaceutical compositions can be in the form of solid form or a semi-solid dosage form that the isolated morphic form is stable in, such as, for example, tablets, suppositories, pills, capsules, powders, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
• the compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.
• compositions of the disclosure can be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal administration or in a form suitable for administration by inhalation or insufflation.
• the preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
• conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
• permeation enhancer excipients including polymers such as: poly cations (chitosan and its quatemaiy ammonium derivatives, poly-L- arginine, animated gelatin); polyanions (JV-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).
• polymers such as: poly cations (chitosan and its quatemaiy ammonium derivatives, poly-L- arginine, animated gelatin); polyanions (JV-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine
• the composition will generally take the form of a tablet or capsule. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added.
• the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
• suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
• Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
• the pharmaceutical formulations can contain other additives, such as pH-adjusting additives.
• useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate.
• the formulations can contain antimicrobial preservatives.
• Useful antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. An antimicrobial preservative is typically employed when the formulations is placed in a vial designed for multi-dose use.
• the pharmaceutical formulations described herein can be lyophilized using techniques well known in the art.
• a pharmaceutical composition can take the form of a tablet, pill, capsule, powder, and the like.
• Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch (e.g., potato or tapioca starch) and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
• binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium lamyl sulfate, and talc are often very useful for tableting purposes.
• Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules.
• compositions also are provided which provide a controlled release of a compound described herein, including through the use of a degradable polymer, as known in the art.
• the additional therapeutic agent described in the Combination Section below is administered as a pharmaceutically acceptable salt, for example, a salt described below.
• salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the presently disclosed compounds. These salts can be prepared during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
• Basic compounds are capable of forming a wide variety of different salts with various inorganic and organic acids. Acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
• the free base forms may differ from their respective salt forms in certain physical properties such as solubility in polar solvents.
• Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N.N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
• the base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
• the free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
• the free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents.
• Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like.
• Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like.
• Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like.
• organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like.
• Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
• Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethyl ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.
• Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active disclosed compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
• Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil, which maintain the stability of the isolated morphic form.
• Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
• Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
• microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin.
• the microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.
• Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven singleZ-multiple dose dry powder inhalers (DPI).
• DPI dry powder inhalers
• the devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers.
• nebulizers include jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung.
• an effective amount of morphic form or composition as described herein is used to treat a medical disorder which is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade) including a complement factor D-related disorder or alternative complement pathway-related disorder, a disorder or abnormality of a cell that adversely affects the ability of the cell to engage in or respond to normal complement activity, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a pharmaceutical or biopharmaceutical drug administration, a blood transfusion, or other allogenic tissue or fluid administration.
• a medical disorder which is an inflammatory or immune condition
• a disorder mediated by the complement cascade including a dysfunctional cascade
• a complement factor D-related disorder or alternative complement pathway-related disorder a disorder or abnormality of a cell that adversely affects the ability of the cell to engage in or respond to normal complement activity, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a
• a method for the treatment of C3 glomerulonephritis includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of paroxysmal nocturnal hemoglobinuria includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of wet or dry age-related macular degeneration (AMD) in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of rheumatoid arthritis in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of multiple sclerosis or amyotrophic lateral sclerosis in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of membranoproliferative glomerulonephritis type P (MPGN II) in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of nonalcoholic steatophepatitis (NASH) in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• NASH nonalcoholic steatophepatitis
• a method for the treatment of fatty liver, liver inflammation, cirrhosis, or liver failure in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of dermatomyositis in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of arthritis or COPD in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of a respiratory disease or a cardiovascular disease in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of atypical or typical hemolytic uremic syndrome in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of membrane proliferative glomerulonephritis or age-related macular degeneration (AMD) in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• a method for the treatment of type I diabetes or complications thereof in a host includes the administration of an effective amount of a morphic form described herein, optionally in a pharmaceutically acceptable composition.
• the morphic form, optionally in a pharmaceutically acceptable composition, as disclosed herein is also useful for administration in combination (in the same or a different dosage form) or alternation with a second pharmaceutical agent for use in ameliorating or reducing a side effect of the second pharmaceutical agent.
• Another embodiment includes the administration of an effective amount of a morphic form, optionally in a pharmaceutically acceptable composition to a host to treat an ocular, pulmonary, gastrointestinal, or other disorder that can benefit from topical or local delivery.
• a morphic form provided herein can be used to treat or prevent a disorder in a host mediated by complement factor D, or by an excessive or detrimental amount of the complement-C3 amplification loop of the complement pathway.
• the invention includes methods to treat or prevent complement associated disorders that are induced by antibody-antigen interactions, a component of an immune or autoimmune disorder or by ischemic injury.
• the invention also provides methods to decrease inflammation or an immune response, including an autoimmune response, where mediated or affected by factor
• the disorder is selected from fatty liver and conditions stemming from fatty liver, such as nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis and liver failure.
• NASH nonalcoholic steatohepatitis
• a method is provided for treating fatty liver disease in a host by administering an effective amount of a morphic form or composition as described herein.
• a morphic form or composition as described herein is used to modulate an immune response prior to or during surgery or other medical procedure.
• One nonlimiting example is use in connection with acute or chronic graft versus host disease, which is a common complication as a result of allogeneic tissue transplant, and can also occur as a result of a blood transfusion.
• the present invention provides a method of treating or preventing dermatomyositis by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein.
• the present invention provides a method of treating or preventing amyotrophic lateral sclerosis by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein. In one embodiment, the present invention provides a method of treating or preventing abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein.
• the present invention provides a method of treating or preventing a C3 glomurenopathy by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein.
• the disorder is selected from dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).
• the present invention provides a method of treating or preventing a IC-MPGN by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein.
• the present invention provides a method of treating or preventing a paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein.
• PNH paroxysmal nocturnal hemoglobinuria
• 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 a morphic form or composition as described herein.
• AMD age-related macular degeneration
• the present invention provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein.
• the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein.
• the present invention provides a method of treating or preventing myasthenia gravis by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein.
• the present invention provides a method of treating or preventing atypical hemolytic uremic syndrome (aHUS) by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein. In one embodiment, the present invention provides a method of treating or preventing neuromyelitis optica (NMO) by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein.
• aHUS atypical hemolytic uremic syndrome
• NMO neuromyelitis optica
• the present invention provides a method of treating or preventing a disorder as described below by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein, including: vitritis, sarcoidosis, syphilis, tuberculosis, or Lyme disease; retinal vasculitis, Bales disease, tuberculosis, syphilis, or toxoplasmosis; neuroretinitis, viral retinitis, or acute retinal necrosis;
• varicella zoster virus herpes simplex virus, cytomegalovirus, Epstein-Barr virus, lichen planus, or Dengue-associated disease (e.g., hemorraghic Dengue Fever); Masquerade syndrome, contact dermatitis, trauma induced inflammation, UVB induced inflammation, eczema, granuloma annulare, or acne.
• Dengue-associated disease e.g., hemorraghic Dengue Fever
• Masquerade syndrome contact dermatitis, trauma induced inflammation, UVB induced inflammation, eczema, granuloma annulare, or acne.
• the disorder is selected from: acute myocardial infarction, aneurysm, cardiopulmonary bypass, dilated cardiomyopathy, complement activation during cardiopulmonary bypass operations, coronary artery disease, restenosis following stent placement, or percutaneous transluminal coronary angioplasty (PTCA); antibody-mediated transplant rejection, anaphylactic shock, anaphylaxis, allogenic transplant, humoral and vascular transplant rejection, graft dysfunction, graft-versus-host disease, Graves' disease, adverse drug reactions, or chronic graft vasculopathy; allergic bronchopulmonary aspergillosis, allergic neuritis, drug allergy, radiation- induced lung injury, eosinophilic pneumonia, radiographic contrast media allergy, bronchiolitis obliterans, or interstitial pneumonia; parkinsonism-dementia complex, sporadic frontotemporal dementia, frontotemporal dementia with Parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, tangle only dementia, cerebral
• the disorder is selected from: atopic dermatitis, dermatitis, dermatomyositis bullous pemphigoid, scleroderma, sclerodermatomyositis, psoriatic arthritis, pemphigus vulgaris, Discoid lupus erythematosus, cutaneous lupus, chilblain lupus erythematosus, or lupus erythematosus-lichen planus overlap syndrome; cryoglobulinemic vasculitis, mesenteric/enteric vascular disorder, peripheral vascular disorder, antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), IL-2 induced vascular leakage syndrome, or immune complex vasculitis;angioedema, low platelets (HELLP) syndrome, sickle cell disease, platelet refractoriness, red cell casts, or typical or infectious hemolytic uremic syndrome (tHUS); hematuria
• the disorder is selected from: wet (exudative) AMD, dry (non- exudative) AMD, chorioretinal degeneration, choroidal neovascularization (CNV), choroiditis, loss of RPE function, loss of vision (including loss of visual acuity or visual field), loss of vision from AMD, retinal damage in response to light exposure, retinal degeneration, retinal detachment, retinal dysfunction, retinal neovascularization (RNV), retinopathy of prematurity, pathological myopia, or RPE degeneration; pseudophakic bullous keratopathy, symptomatic macular degeneration related disorder, optic nerve degeneration, photoreceptor degeneration, cone degeneration, loss of photoreceptor cells, pars planitis, scleritis, proliferative vitreoretinopathy, or formation of ocular drusen; chronic urticaria, Churg-Strauss syndrome, cold agglutinin disease (CAD), cortico
• the disorder is selected from: hyperlipidemia, hypertension, hypoalbuminemia, hypobolemic shock, hypocomplementemic urticarial vasculitis syndrome, hypophosphastasis, hypovolemic shock, idiopathic pneumonia syndrome, or idiopathic pulmonary fibrosis; inclusion body myositis, intestinal ischemia, iridocyclitis, ulceris, juvenile chronic arthritis, Kawasaki's disease (arteritis), or lipiduria; membranoproliferative glomerulonephritis (MPGN) I, microscopic polyangiitis, mixed ciyoglobulinemia, molybdenum cofactor deficiency (MoCD) type A, pancreatitis, panniculitis, Pick's disease, polyarteritis nodosa (PAN), progressive subcortical gliosis, proteinuria, reduced glomerular filtration rate (GFR), or renovascular disorder; multiple organ failure, multiple organ failure, multiple organ
• a morphic form or composition as described herein is useful for treating or preventing a disorder selected from autoimmune oophoritis, endometriosis, autoimmune orchitis, Ord’s thyroiditis, autoimmune enteropathy, coeliac disease, Hashimoto’s encephalopathy, antiphospholipid syndrome (APLS) (Hughes syndrome), aplastic anemia, autoimmune lymphoproliferative syndrome (Canale-Smith syndrome), autoimmune neutropenia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adipose dolorosa (Dercum’s disease), adult onset Still’s disease, ankylosing spondylitis, CREST syndrome, drug- induced lupus, eosinophilic fasciitis (Shulman’s syndrome), Felty syndrome, IgG4-related disease, mixed connective tissue disease (MCTD), palindromic rheumatism (Hench-R
• eye disorders that may be treated according to the compositions and methods disclosed herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchorcercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs' endothelial dystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases, environmental dry eye diseases, corneal neovascularization diseases, post-comeal transplant rejection prophylaxis and treatment, autoimmune uveitis, infectious uveitis, posterior uveitis (including toxoplasmosis), pan-uveitis, an inflammatoiy disease of the vitreous or retina, endophthalmitis prophylaxis and treatment, macular edema, macular degeneration, age related macular degeneration, proliferative and nonproliferative diabetic
• the disorder is selected from glaucoma, diabetic retinopathy, blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatrical pemphigoid, uveitis, adult macular degeneration, diabetic retinopa retinitis pigmentosa, macular edema, diabetic 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, postoperative inflammation, and retinal vein occlusion, or central retinal vein occulusion (CVRO).
• glaucoma including bullous pemphigo
• complement mediated diseases include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), respiratory diseases, cardiovascular diseases.
• ophthalmic diseases including early or neovascular age-related macular degeneration and geographic atrophy
• autoimmune diseases including arthritis, rheumatoid arthritis
• respiratory diseases including cardiovascular diseases.
• the compounds of the invention are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.
• Disorders that may be treated or prevented by a morphic form or composition as described herein also include, but are not limited to: hereditary angioedema, capillary leak syndrome, hemolytic uremic syndrome (HUS), neurological disorders, Guillain Barre Syndrome, diseases of the central nervous system and other neurodegenerative conditions, glomerulonephritis (including membrane proliferative glomerulonephritis), SLE nephritis, proliferative nephritis, liver fibrosis, tissue regeneration and neural regeneration, or Barraquer- Simons Syndrome; inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), disorders of inappropriate or undesirable complement activation, interieukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, system lupus erythematosus (SLE), lupus nephritides, arthritis, immune complex disorders and autoimmune diseases, systemic lupus, or lupus erythe
• ARDS acute respiratory distress syndrome
• COPD chronic obstructive pulmonary disease
• 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, sulfirr dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., bum, freeze), bronchoconstriction, hypersensitivity pneu
• a method for the treatment of sickle cell in a host includes the administration of an effective amount of a morphic form or composition as described herein.
• a method for the treatment of immunothrombocytopenic purpura (GGR), thrombotic thrombocytopenic purpura (TTP), or idiopathic thrombocytopenic purpura (GGR) in a host includes the administration of an effective amount of a morphic form or composition as described herein.
• a method for the treatment of ANCA-vasculitis in a host includes the administration of an effective amount of a morphic form or composition as described herein.
• a method for the treatment of IgA nephropathy in a host includes the administration of an effective amount of a morphic form or composition as described herein.
• a method for the treatment of rapidly progressing glomerulonephritis (RPGN) in a host is provided that includes the administration of an effective amount of a morphic form or composition as described herein.
• RPGN rapidly progressing glomerulonephritis
• a method for the treatment of lupus nephritis in a host is provided that includes the administration of an effective amount of a morphic form or composition as described herein.
• a method for the treatment of hemorraghic dengue fever, in a host is provided that includes the administration of an effective amount of a morphic form or composition as described herein.
• a morphic form or composition as described herein is used in the treatment of an autoimmune disorder.
• the complement pathway enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the body. It is part of the innate immune system and in healthy individuals is an essential process. Inhibiting the complement pathway will decrease the body’s immune system response. Therefore, it is an object of the present invention to treat autoimmune disorders by administering an effective does of a morphic form or composition as described herein to a subject in need thereof.
• the autoimmune disorder is caused by activity of the complement system. In one embodiment the autoimmune disorder is caused by activity of the alternative complement pathway. In one embodiment the autoimmune disorder is caused by activity of the classical complement pathway. In another embodiment the autoimmune disorder is caused by a mechanism of action that is not directly related to the complement system, such as the overproliferation of T-lymphocytes or the over-production of cytokines.
• Non-limiting examples of autoimmune disorders include: lupus, allograft rejection, autoimmune thyroid diseases (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel diseases (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis, and scleroderma.
• autoimmune thyroid diseases such as Graves' disease and Hashimoto's thyroiditis
• autoimmune uveoretinitis giant cell arteritis
• inflammatory bowel diseases including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis
• diabetes
• a morphic form or composition as described herein is used in the treatment of lupus.
• lupus include lupus erythematosus, cutaneous lupus, discoid lupus erythematosus, chilblain lupus erythematosus, or lupus erythematosus-lichen planus overlap syndrome.
• Lupus erythematosus is a general category of disease that includes both systemic and cutaneous disorders.
• the systemic form of the disease can have cutaneous as well as systemic manifestations.
• SLE is an inflammatory disorder of unknown etiology that occurs predominantly in women, and is characterized by articular symptoms, butterfly erythema, recurrent pleurisy, pericarditis, generalized adenopathy, splenomegaly, as well as CNS involvement and progressive renal failure.
• the sera of most patients (over 98%) contain antinuclear antibodies, including anti-DNA antibodies. High titers of anti-DNA antibodies are essentially specific for SLE. Conventional treatment for this disease has been the administration of corticosteroids or immunosuppressants.
• DLE chronic cutaneous lupus
• subacute cutaneous lupus subacute cutaneous lupus
• acute cutaneous lupus a disfiguring chronic disorder primarily affecting the skin with sharply circumscribed macules and plaques that display erythema, follicular plugging, scales, telangiectasia and atrophy. The condition is often precipitated by sun exposure, and the early lesions are erythematous, round scaling papules that are 5 to 10 mm in diameter and display follicular plugging.
• DLE lesions appear most commonly on the cheeks, nose, scalp, and ears, but they may also be generalized over the upper portion of the trunk, extensor surfaces of the extremities, and on the mucous membranes of the mouth. If left untreated, the central lesion atrophies and leaves a scar. Unlike SLE, antibodies against double-stranded DNA (e.g., DNA-binding test) are almost invariably absent in DLE.
• MS multiple Sclerosis is an autoimmune demyelinating disorder that is believed to be T lymphocyte dependent.
• MS generally exhibits a relapsing-remitting course or a chronic progressive course.
• the etiology of MS is unknown, however, viral infections, genetic predisposition, environment, and autoimmunity all appear to contribute to the disorder.
• Lesions in MS patients contain infiltrates of predominantly T lymphocyte mediated microglial cells and infiltrating macrophages.
• CD4+ T lymphocytes are the predominant cell type present at these lesions.
• the hallmark of the MS lesion is plaque, an area of demyelination sharply demarcated from the usual white matter seen in MRI scans. Histological appearance of MS plaques varies with different stages of the disease.
• MOG myelin oligodendrocyte glycoprotein
• Diabetes can refer to either type 1 or type 2 diabetes.
• a morphic form or composition as described herein is provided at an effective dose to treat a patient with type 1 diabetes.
• a morphic form or composition as described herein is provided at an effective dose to treat a patient with type 2 diabetes.
• Type 1 diabetes is an autoimmune disease. An autoimmune disease results when the body's system for fighting infection (the immune system) attacks a part of the body. In the case of diabetes type 1, the pancreas then produces little or no insulin.
• the present invention provides a method of treating or preventing a IC-MPGN by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• the present invention provides a method of treating or preventing a delayed graft function (DGF) by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• DGF delayed graft function
• the present invention provides a method of treating or promoting wound healing by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein
• the present invention provides a method of treating or preventing a HSCT-TMA by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• the present invention provides a method of treating or preventing a paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount a moprhic form or composition as described herein.
• PNH paroxysmal nocturnal hemoglobinuria
• 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 a moprhic form or composition as described herein.
• AMD age-related macular degeneration
• the present invention provides a method of treating or preventing macular dystrophy by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein. In some embodiments, the present invention provides a method of treating or preventing a Crohn’s disease by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• the present invention provides a method of treating or preventing Stargardt’s disease (Stargardt macular dystrophy) by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• the present invention provides a method of treating or preventing acute pancreatitis by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• the present invention provides a method of treating or preventing asthma (TH2) or asthma (non-TH2) by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• the present invention provides a method of treating or preventing periodontitis by administering to a subject in need thereof an effective amount of a moprhic form or compositi on as described herein .
• the present invention provides a method of treating or preventing a diabetic retinopathy by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• the present invention provides a method of treating or preventing a hidradenitis suppurativa by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• the present invention provides a method of treating or preventing acute respiratory distress syndrome (ARDS) by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• ARDS acute respiratory distress syndrome
• tire present invention provides methods of treating or preventing a nephrology disorder selected from acute kidney injury (AKI), idiopathic membranous nephropathy, IgA nephropathy (IgAN) lupus nephritis (LN), and primary' focal segmental glomerulosclerosis by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• the present invention provides methods of treating or preventing preeclampsia by administering to a subject in need thereof an effective amount of a moprhic form or composition as described herein.
• a morphic form or composition as described herein may be provided in combination or alternation with or preceded by, concomitant with or followed by, an effective amount of at least one additional therapeutic agent, for example, for treatment of a disorder listed herein.
• additional therapeutic agent for example, for treatment of a disorder listed herein.
• second active agents for such combination therapy are provided below.
• a morphic form or composition as described herein may be provided in combination or alternation with at least one additional inhibitor of the complement system or a second active compound with a different biological mechanism of action.
• a morphic form or composition as described herein may be provided together with a protease inhibitor, a soluble complement regulator, a therapeutic antibody (monoclonal or polyclonal), complement component inhibitor, receptor agonist, or siRNA.
• a morphic form described herein is administered in combination or alternation with an antibody against tumor necrosis factor (TNF), including but not limited to infliximab (Remicade), adalimumab, certolizumab, golimumab, or a receptor fusion protein such as etanercept (Embrel).
• TNF tumor necrosis factor
• a morphic form as described herein can be administered in combination or alternation with an anti-CD20 antibody, including but not limited to rituximab (Rituxan), adalimumab (Humira), ofatumumab (Arzerra), tositumomab (Bexxar), obinutuzumab (Gazy va), or ibritumomab (Zevalin).
• an anti-CD20 antibody including but not limited to rituximab (Rituxan), adalimumab (Humira), ofatumumab (Arzerra), tositumomab (Bexxar), obinutuzumab (Gazy va), or ibritumomab (Zevalin).
• a morphic form as described herein can be administered in combination or alternation with an anti-IL6 antibody, including but not limited to tocilizumab (Actemra) and siltuximab (Sylvant).
• an anti-IL6 antibody including but not limited to tocilizumab (Actemra) and siltuximab (Sylvant).
• a morphic form as described herein can be administered in combination or alternation with an IL17 inhibitor, including but not limited to secukibumab (Cosentyx).
• a morphic form as described herein can be administered in combination or alternation with a p40 (IL12/IL23) inhibitor, including but not limited to ustekinumab (Stelara).
• a morphic form as described herein can be administered in combination or alteration with an IL23 inhibitor, including but not limited to risankizumab.
• a morphic form as described herein can be administered in combination or alteration with an anti-interferon a antibody, for example but not limited to sifalimumab.
• a morphic form as described herein can be administered in combination or alteration with a kinase inhibitor, for example but not limited to a JAK1/JAK3 inhibitor, for example but not limited to tofacitinib (Xelianz).
• a morphic form as described herein can be administered in combination or alteration with a JAK1/JAK2 inhibitor, for example but not limited to baracitibib.
• a morphic form as described herein can be administered in combination or alteration with an anti-VEGF agent, for example but not limited to: aflibercept (Eylea®; Regeneron Pharmaceuticals); ranibizumab (Lucentis®: Genentech and Novartis); pegaptanib (Macugen®; OSI Pharmaceuticals and Pfizer); bevacizumab (Avastin; Genentech/Roche); lapatinib (Tykerb); sunitinib (Sutent); axitinib (Inlyta); pazopanib; sorafenib (Nexavar); ponatinib (Inclusig); regorafenib (Stivarga); cabozantinib (Abometyx; Cometriq); vendetanib (Caprelsa); ramucirumab (Cyramza); lenvatinib (Lenvima); ziv-aflibercept (Eylea
• a morphic form as described herein can be administered in combination or alternation with an immune checkpoint inhibitor.
• checkpoint inhibitors include anti-PD-1 or anti-PDLl antibodies, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and Medlmmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 /VISTA inhibitor CA-170 (Curis Inc.), atezolizumab, durvalumab, and KN035, or anti-CTLA4 antibodies , for example Ipilimumab, Tremelimumab, AGEN1884 and AGEN
• Protease inhibitors plasma-derived C7-INH concentrates, for example Cetor® (Sanquin), Berinert- P® (CSL Behring, Lev Pharma), and Cinryze®; recombinant human Cl -inhibitors, for example Rhucin®; ritonavir (Norvii®, Abbvie, Inc.);
• Soluble complement regulators Soluble complement receptor 1 ( TP10 ) (Avant Immunotherapeutics); sCRl-sLe x /TP-20 (Avant Immunotherapeutics); MLN-2222 ! CAB-2 (Millenium Pharmaceuticals); Mirococept (Inflazyme Pharmaceuticals);
• Therapeutic antibodies Eculizumab/Soliris (Alexion Pharmaceuticals); Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234 (Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2 Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (Genmab A/S);
• Complement component inhibitors Compstatin/POT-4 (Potentia Pharmaceuticals); ARC 1905 (Archemix); 4(lMEW)APL-l,APL-2 (Appelis); CP40/AMY-101,PEG-Cp40 (Amyndas);
• PDGF inhibitors Sorafenib Tosylate; Imatinib Mesylate (STI571); Sunitinib Malate; Ponatinib (AP24534); Axitinib; Imatinib (STI571); Nintedanib (BIBF 1120); Pazopanib HC1 (GW786034 HC1); Dovitinib (TKI-258, CHIR-258); Linifanib (ABT-869); Crenolanib (CP- 868596); Masitinib (AB1010); Tivozanib (AV-951); Motesanib Diphosphate (AMG-706); Amuvatinib (MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751; Telatinib; PP121; Pazopanib; KRN 633; Dovitinib (TKI-258) Dilactic Acid; MK-2461; Tyrphostin (AG 1296); Dovitini
• Anti-factor H or anti-factor B agents Anti-FB siRNA (Alnylam); FCFD4514S (Genentech/Roche) SOMAmers for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301 (Amyndas);
• Complement C3 or CAP C3 Convertase targeting molecules TT30 (CR2/CFH) (Alexion); TT32 (CR2/CR1) (Alexion Pharmaceuticals); Nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Bikaciomab, NM9308 (Novelmed); CVF, HC-1496 (InCode)
• ALXN1102/ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); H17 C3 (C3b/iC3b) (EluSys Therapeutics); Mini-CFH (Amyndas) Mirococept (APT070); sCRl (CDX- 1135) (Celldex); CRIg/CFH; Anti-CR3, anti-MASP2, anti Cls, and anti-Cln molecules: Cynryze (ViroPharma/Baxter); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera);
• Receptor agonists PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini);
• Recombinant human MBL ihMBL; Enzon Pharmaceuticals
• Imides and glutarimide derivatives such as thalidomide, lenalidomide, pomalidomide
• Additional nonlimiting examples that can be used in combination or alternation with a m orphic form or composition as described herein include the following.
• TT32 (CR2/CR1) CAP and CCP Alexion CR1 -based protein
• a morphic form or composition as described herein may be provided together with a compound that inhibits an enzyme that metabolizes an administered protease inhibitor.
• a morphic form may be provided together with ritonavir.
• a morphic form or composition as described herein may be provided in combination with a complement C5 inhibitor or C5 convertase inhibitor.
• a morphic form or composition as described herein may be provided in combination with eculizumab, a monoclonal antibody directed to the complement factor C5 and manufactured and marketed by Alexion Pharmaceuticals under the tradename Soliris. Eculizumab has been approved by the U.S. FDA for the treatment of PNH and aHUS.
• a morphic form or composition as described herein may be provided together with a compound that inhibits Complement Factor D.
• a morphic form or composition as described herein as described herein can be used in combination or alternation with a compound described in Biocryst Pharmaceuticals US Pat. No.
• a morphic form or composition as described herein is administered in combination with an anti-inflammatory drug, antimicrobial agent, anti-angiogenesis agent, immunosuppressant, antibody, steroid, ocular antihypertensive drug or combinations thereof.
• agents include amikacin, anecortane acetate, anthracenedione, anthracycline, an azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, clortrimazole, a clotrimazole cephalosporin, corticosteroids, dexamethasone, desamethazone, econazole, eftazidime, epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides, imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin, neomycin, n
• a morphic form or composition as described herein can be administered in combination or alternation with at least one immunosuppressive agent.
• the immunosuppressive agent as non-limiting examples, may be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g.
• Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a SIP receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4,
• anti-inflammatory agents examples include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam, meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofe
• a morphic form or composition as described herein is combined with one or more non-steroidal antiinflammatory drugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate (Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine (Toradol), naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren), and combinations thereof.
• NSAIDs non-steroidal antiinflammatory drugs
• a morphic form or composition as described herein is administered in combination or alteration with an omega-3 fatty acid or a peroxisome proliferator-activated receptor (PPARs) agonist.
• Omega-3 fatty acids are known to reduce serum triglycerides by inhibiting DGAT and by stimulating peroxisomal and mitochondrial beta oxidation.
• Two omega- 3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been found to have high affinity for both PPAR-alpha and PPAR-gamma.
• Marine oils e.g., fish oils, are a good source of EPA and DHA, which have been found to regulate lipid metabolism.
• Omega-3 fatty acids have been found to have beneficial effects on the risk factors for cardiovascular diseases, especially mild hypertension, hypertriglyceridemia and on the coagulation factor VH phospholipid complex activity.
• Omega-3 fatty acids lower serum triglycerides, increase serum HDL- cholesterol, lower systolic and diastolic blood pressure and the pulse rate, and lower the activity of the blood coagulation factor VH-phospholipid complex.
• omega-3 fatty acids seem to be well tolerated, without giving rise to any severe side effects.
• One such form of omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA and is sold under the trademark Omacor®.
• Such a form of omega- 3 fatty acid is described, for example, in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, the disclosures of which are incorporated herein by reference.
• Peroxisome proliferator-activated receptors are members of the nuclear hormone receptor superfamily ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. There are three distinct PPAR subtypes that are the products of different genes and are commonly designated PPAR-alpha, PPAR-beta/delta (or merely, delta) and PPAR-gamma.
• PPAR agonists e.g., PPAR-alpha agonists, PPAR-gamma agonists and PPAR-delta agonists.
• Some pharmacological agents are combinations of PPAR agonists, such as alpha/gamma agonists, etc., and some other pharmacological agents have dual agonist/antagonist activity.
• Fibrates such as fenofibrate, bezafibrate, clofibrate and gemfibrozil, are PPAR-alpha agonists and are used in patients to decrease lipoproteins rich in triglycerides, to increase HDL and to decrease atherogenic-dense LDL. Fibrates are typically orally administered to such patients.
• Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester has been known for many years as a medicinally active principle because of its efficacy in lowering blood triglyceride and cholesterol levels.
• 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 a morphic form or composition as described herein in combination with an anti-VEGF agent.
• anti-VEGF agents include, but are not limited to, aflibercept (Eylea®; Regeneron Pharmaceuticals); ranibizumab (Lucentis®: Genentech and Novartis); pegaptanib (Macugen®; OSI Pharmaceuticals and Pfizer); bevacizumab (Avastin; Genentech/Roche); lapatinib (Tykerb); sunitinib (Sutent); axitinib (Inlyta); pazopanib; sorafenib (Nexavar); ponatinib (Inclusig); regorafenib (Sti varga); Cabozantinib (Abometyx; Cometriq);
• 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 a morphic form or composition as described herein in combination with a complement C5 inhibitor, for example, a complement C5 inhibitor described herein and in the table above titled Non-limiting examples of potential therapeutics for combination therapy, including, but not limited to, eculizumab; LFG316 (Novartis/Morphosys); Anti-C5 siRNA (Alnylam); ARC 1005 (Novo Nordisk); Coversin (Volution Immuno-Pharmaceuticals); Mubodine (Adienne Pharma); RA101348 (Ra Pharma); SOB 1002 (Swedish Orphan Biovitrum); SOMAmers (SomaLogic); Erdigna (Adienne Pharma); ARC 1905 (Opthotech); MEDI7814 (Medlmmune); NOX-D19 (Noxxon); IFX-1, CaCP
• 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 a morphic form or composition as described herein in combination with anti- properidin agent, for example, an anti-properidin agent as described above, including but not limited to NM9401 (Novelmed).
• AMD age-related macular degeneration
• 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 a morphic form or composition as described herein in combination with a complement C3 inhibitor for example, a complement C3 inhibitor described above, including, but not limited to, a compstatin or compstatin analogue, for example Compstatin/POT-4 (Potentia Pharmaceuticals); ARC 1905 (Archemix); 4(lMEW)APL-l,APL-2 (Appelis); CP40/AMY-101,PEG-Cp40 (Amyndas) Complement C3 or CAP C3 Convertase targeting molecules: TT30 (CR2/CFH) (Alexion); TT32 (CR2/CR1) (Alexion Pharmaceuticals);
• a complement C3 inhibitor for example, a complement C3 inhibitor described above, including, but not limited to, a compstatin or compstatin analogue, for example Compstatin/POT-4 (Po
• Nafamostat FUT-175, Futhan
• Bikaciomab NM9308 (Novelmed); CVF, HC-1496 (InCode) ALXN1102/ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Optherion); HI 7 C3 (C3b/iC3b) (EluSys Therapeutics); Mini-CFH (Amyndas) Mirococept (APT070); sCRl (CDX-1135) (Celldex); and CRIg/CFH.
• 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 a morphic form or composition as described herein in combination with an anti-factor H or anti-factor B agent selected from Anti-FB siRNA (Alnylam); FCFD4514S (Genentech/Roche) SOMAmers for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301 (Amyndas).
• AMD age-related macular degeneration
• 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 a morphic form or composition as described herein in combination with an anti-MASP2, anti-Cls or anti-CR3 molecules, for example, but not limited to: Cynryze (ViroPharma/Baxter); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera).
• AMD age-related macular degeneration
• 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 a morphic form or composition as described herein in combination with an PDGF inhibitor, for example as described herein including but not limited to Sorafenib Tosylate; Imatinib Mesylate (STI571); Sunitinib Malate; Ponatinib (AP24534); Axitinib; Imatinib (STI571); Nintedanib (BIBF 1120); Pazopanib HC1 (GW786034 HC1); Dovitinib (TKI-258,
• the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein with an additional inhibitor of the complement system or another active compound with a different biological mechanism of action.
• the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein in combination or alternation with eculizumab.
• the present invention provides a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein in combination or alternation with CP40.
• the additional agent is PEGylated-CP40.
• CP40 is a peptide inhibitor that shows a strong binding affinity for C3b and inhibits hemolysis of paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes.
• the additional agent is a complement component inhibitor, for example but not limited to Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(lMEW)APL-l,APL-2 (Appelis); CP40/AMY-101,PEG-Cp40 (Amyndas); a PDGF inhibitor, for example, but not limited to Sorafenib Tosylate; Imatinib Mesylate (STI571); Sunitinib Malate; Ponatinib (AP24534); Axitinib; Imatinib (8 ⁇ 571); Nintedanib (BIBF 1120); Pazopanib HC1 (GW786034 HC1); Dovitinib (TKI-258, CHIR-258); Linifanib (ABT-869); Crenolanib (CP- 868596); Masitinib (AB1010); Tivozanib (AV-951); Motesanib Diphosphate (AMG), CC
• the present invention provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a composition comprising a morphic form or composition as described herein in combination or alternation with an additional inhibitor of the complement system, or an active agent that functions through a different mechanism of action.
• the present invention provides a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein in combination or alternation with methotrexate.
• a morphic form or composition as described herein is administered in combination or alternation with at least one additional therapeutic agent selected from: salicylates including aspirin (Anacin, Ascriptin, Bayer Aspirin, Ecotrin) and salsalate (Mono-Gesic, Salgesic); nonsteroidal anti-inflammatory drugs (NSAIDs); nonselective inhibitors of the cyclo-oxygenase (COX-1 and COX-2) enzymes, including diclofenac (Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis), naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine), indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam (Mobic); selective cyclo-oxygenase-2 (COX-2) inhibitors including Celecoxib (Anacin,
• the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein in combination or alternation with an additional inhibitor of the complement system, or an active agent that functions through a different mechanism of action.
• the present invention provides a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a morphic form or composition as described herein in combination or alternation with a corticosteroid.
• corticosteroids include, but are not limited to, prednisone, dexamethasone, solumedrol, and methylprednisolone.
• a morphic form or composition as described herein is combined with at least one anti-multiple sclerosis drug, for example, selected from: Aubagio (teriflunomide), Avonex (interferon beta- la), Betaseron (interferon beta- lb), Copaxone (glatiramer acetate), Extavia (interferon beta- lb), Gilenya (fingolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone), Plegridy (peginterferon beta-la), Rebif (interferon beta-la), Tecfidera (dimethyl fumarate), Tysabri (natalizumab), Solu- Medrol (methylprednisolone), High-dose oral Deltasone (prednisone), H.P. Acthar Gel (ACTH), or a combination thereof.
• Aubagio teriflunomide
• Avonex interferon beta- la
• Betaseron interferon
• a morphic form or composition as described herein may be provided in combination with eculizumab for the treatment of PNH, aHUSs, STEC-HUS, ANCA-vasculitis, AMD, CAD, C3 glomerulopathy, for example DDD or C3GN, chronic hemolysis, neuromyelitis optica, or transplantation rejection.
• a morphic form or composition as described herein may be provided in combination with compstatin or a compstatin derivative for the treatment of PNH, aHUSs, STEC-HUS, ANCA- vasculitis, AMD, CAD, C3 glomerulopathy, for example DDD or C3GN, chronic hemolysis, neuromyelitis optica, or transplantation rejection.
• the additional agent is a complement component inhibitor, for example but not limited to Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(lMEW)APL-l,APL-2 (Appelis); CP40/AMY- 101,PEG-Cp40 (Amyndas); a PDGF inhibitor, for example, but not limited to Sorafenib Tosylate; Imatinib Mesylate (STI571); Sunitinib Malate; Ponatinib (AP24534); Axitinib; Imatinib (STI571); Nintedanib (BIBF 1120); Pazopanib HC1 (GW786034 HC1); Dovitinib (TKI- 258, CHIR-258); Linifanib (ABT-869); Crenolanib (CP-868596); Masitinib (AB1010);
• a complement component inhibitor for example but not limited to Compstatin/POT-4 (Po
• Tivozanib (AV-951); Motesanib Diphosphate (AMG-706); Amuvatinib (MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751; Telatinib; PP121; Pazopanib; KRN 633; Dovitinib (TKI-258) Dilactic Acid; MK-2461; Tyrphostin (AG 1296); Dovitinib (TKI258) Lactate; Sennoside B; Sunitinib; AZD2932; and Trapidil; an anti-factor H or anti-factor B agent, for example anti-FB siRNA (Alnylam); FCFD4514S (Genentech/Roche) SOMAmers for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301 (Amyndas); a complement C3 or CAP C3 convertase taigeting molecule, for example but not limited to TT30 (
• a morphic form or composition as described herein may be provided in combination with rituxan for the treatment of a complement mediated disorder.
• the complement mediated disorder is, for example, rheumatoid arthritis, Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis), and Microscopic Polyangiitis (MPA).
• the disorder is Lupus.
• a morphic form or composition as described herein may be provided in combination with cyclophosphamide for the treatment of a complement mediated disorder.
• the disorder is an autoimmune disease.
• the complement mediated disorder is, for example, rheumatoid arthritis, Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis), and Microscopic Polyangiitis (MPA).
• the disorder is Lupus.
• a morphic form or composition as described herein is dosed in combination with a conventional DLE treatment for the treatment of lupus to a subject in need thereof.
• Examples of conventional DLE treatments include topical corticosteroid ointments or creams, such as triamcinolone acetonide, fluocinolone, flurandrenolide, betamethasone valerate, or betamethasone dipropionate. Resistant plaques can be injected with an intradermal corticosteroid. Other potential DLE treatments include calcineurin inhibitors such as pimecrolimus cream or tacrolimus ointment. Particularly resistant cases can be treated with systemic antimalarial drugs, such as hydroxychloroquine (PLAQUENIL).
• PDAQUENIL systemic antimalarial drugs
• a morphic form or composition as described herein may be provided in combination with methotrexate for the treatment of Lupus.
• a morphic form or composition as described herein may be provided in combination with azathioprine for the treatment of Lupus.
• a morphic form or composition as described herein may be provided in combination with a non-steroidal anti-inflammatory drug for the treatment of Lupus.
• a morphic form or composition as described herein may be provided in combination with a corticosteroid for the treatment of Lupus.
• a morphic form or composition as described herein may be provided in combination with a belimumab (Benlysta) for the treatment of Lupus.
• a morphic form or composition as described herein may be provided in combination with hydroxychloroquine (Plaquenil) for the treatment of Lupus.
• hydroxychloroquine Plaquenil
• a morphic form or composition as described herein may be provided in combination with sifalimumab for the treatment of Lupus.
• a morphic form or composition as described herein may be provided in combination with OMS721 (Omeros) for the treatment of a complement mediated disorder.
• a morphic form or composition as described herein may be provided in combination with OMS906 (Omeros) for the treatment of a complement mediated disorder.
• the complement mediated disorder is, for example, thrombotic thrombocytopenic purpura (TTP) or aHUS.
• a morphic form or composition as described herein may be provided in combination with an anti-inflammatory agent, immunosuppressive agent, or anti-cytokine agent for the treatment or prevention of cytokine or inflammatoiy reactions in response to the administration of pharmaceuticals or biotherapeutics (e.g. adoptive T-cell therapy (ACT) such as CAR T-cell therapy, or monoclonal antibody therapy).
• an anti-inflammatory agent e.g., immunosuppressive agent, or anti-cytokine agent for the treatment or prevention of cytokine or inflammatoiy reactions in response to the administration of pharmaceuticals or biotherapeutics (e.g. adoptive T-cell therapy (ACT) such as CAR T-cell therapy, or monoclonal antibody therapy).
• ACT adoptive T-cell therapy
• a morphic form or composition as described herein may be provided in combination with a corticosteroid, for example prednisone, dexamethasone, solumedrol, and methylprednisolone, and/or anti-cytokine compounds targeting, e.g., IL-4, IL-10, IL-11, IL-13 and TGFp.
• a corticosteroid for example prednisone, dexamethasone, solumedrol, and methylprednisolone
• anti-cytokine compounds targeting e.g., IL-4, IL-10, IL-11, IL-13 and TGFp.
• a morphic form or composition as described herein may be provided in combination with an anti-cytokine inhibitor including, but are not limited to, adalimumab, infliximab, etanercept, protopic, efalizumab, alefacept, anakinra, siltuximab, secukibumab, ustekinumab, golimumab, and tocilizumab, or a combination thereof.
• an anti-cytokine inhibitor including, but are not limited to, adalimumab, infliximab, etanercept, protopic, efalizumab, alefacept, anakinra, siltuximab, secukibumab, ustekinumab, golimumab, and tocilizumab, or a combination thereof.
• Additional anti-inflammatory agents that can be used in combination with a morphic form or composition as described herein include, but are not limited to, non-steroidal anti-inflammatory drug(s) (NSAJDs); cytokine suppressive anti-inflammatory drug(s) (CSAIDs); CDP-571/BAY-10-3356 (humanized anti-TNFa antibody; Celltech/Bayer); cA2/infliximab (chimeric anti-TNFa antibody; Centocor); 75 kdTNFR-IgG/etanercept (75 kD TNF receptor-IgG fusion protein; hnmunex); 55 kdTNF-IgG (55 kD TNF receptor-IgG fusion protein; Hoffmann-LaRoche); IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody; IDEC/SmithKline); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion proteins; Seragen); Anti
• a morphic form or composition as described herein may be provided in combination with a corticosteroid for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
• a morphic form or composition as described herein may be provided in combination with etamercept for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
• a morphic form or composition as described herein may be provided in combination with tocilizumab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
• a morphic form or composition as described herein may be provided in combination with etamercept and tocilizumab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
• a morphic form or composition as described herein may be provided in combination with infliximab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
• a morphic form or composition as described herein may be provided in combination with golimumab for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceuticals or biotherapeutics.
• a C5 inhibitor in combination or alternation with an effective amount of a CFD inhibitor selected from Formula I or Formula P.
• the factor D mediated disorder is PNH.
• the C5 inhibitor is a monoclonal antibody targeting C5.
• the C5 inhibitor is eculizumab (SolirisTM Alexion Pharmaceuticals, New Haven, CT, see, e.g., U.S. Patent No. 9,352,035).
• the C5 inhibitor is ravulizumab.
• the C5 inhibitor is a small molecule pharmaceutical.
• the C5 inhibitor is an antibody.
• the C5 inhibitor is a polyclonal antibody targeting C5.
• the C5 inhibitor is an aptamer.
• the C5 inhibitor may be, but is not limited to: a recombinant human minibody, for example Mubodina® (monoclonal antibody, Adienne Pharma and Biotech, Bergamo, Italy; see U.S. Patent No. 7,999,081); coversin (small animal protein, Volution Immuno-pharmaceuticals, Geneva, Switzerland; see e.g. Penabad et al. Lupus, 2012, 23(12): 1324-6); LFG316 (monoclonal antibody, Novartis, Basel, Switzerland, and Morphosys, Planegg, Germany; see U.S. Patent Nos.
• Mubodina® monoclonal antibody, Adienne Pharma and Biotech, Bergamo, Italy
• coversin small animal protein, Volution Immuno-pharmaceuticals, Geneva, Switzerland; see e.g. Penabad et al. Lupus, 2012, 23(12): 1324-6
• LFG316 monoclonal antibody, Novartis, Basel, Switzerland, and Morpho
• ARC-1905 pegylated RNA aptamer, Ophthotech, Princeton, NJ and New York, NY; see Keefe et al., Nature Reviews Drug Discovery, 9, 537-550
• RA101348 and RA101495 microcyclic peptides, Ra Pharmaceuticals, Cambridge, MA
• SOBI002 affibody, Swedish Orphan Biovitrum, Sweden
• ALN- CC5 Si-RNA, Alnylam Pharmaceuticals, Cambridge, MA
• ARC1005 aptamers, Novo Nordisk, Bagsvaerd, Denmark
• SOMAmers aptamers, SomaLogic, Boulder, Co
• SSL7 bacterial protein toxin, see, e.g.
• RG6107 anti-C5 recycling antibody, Roche Pharmaceuticals, Basel, Switzerland
• Ravulizumab ALXN1210
• ALXN5500 monoclonal antibodies, Alexion Pharmaceuticals, New Haven, CT
• TT30 fusion protein, Alexion Pharmaceuticals, New Haven, CT
• REGN3918 monoclonal antibody, Regeneron, Tarrytown, NY
• ABP959 eculizumab biosimilar, Amgen, Thousand Oaks, CA
• the C5 inhibitor is a recombinant human minibody, for example Mubodina®.
• Mubodina® is a fully human recombinant antibody C5 developed by Adienne Pharma and Biotech. Mubodina® is described in U.S. Patent No. 7,999,081.
• the C5 inhibitor is coversin.
• Coversin is a recombinant protein derived from a protein discovered in the saliva of the Ornithodoros moubata tick currently developed as a recombinant protein by Akari Therapeutics. Coversin is described in Penabad et al. Lupus 2012, 23(12): 1324-6.
• the C5 inhibitor is Tesidolumab/LFG316. Tesidolumab is a monoclonal antibody developed by Novartis and Morphosys. Tesidolumab is described in U.S. Patent Nos. 8,241,628 and 8,883,158.
• the C5 inhibitor is ARC- 1905.
• ARC- 1905 is a pegylated RNA aptamer developed by Ophthotech. ARC-1905 is described in Keefe et al. Nature Reviews Drug Discovery, 9:537-550.
• the C5 inhibitor is RA101348.
• RA101348 is a macrocyclic peptide developed by Ra Pharmaceuticals.
• the C5 inhibitor is RA101495.
• RA101495 is a macrocyclic peptide developed by Ra Pharmaceuticals.
• the C5 inhibitor is SOBI002.
• SOBI002 is an affibody developed by the Swedish Orphan Biovitrum.
• the C5 inhibitor is ARC 1005.
• ARC 1005 is an aptamer developed by
• the C5 inhibitor is SOMAmers for C5.
• SOMAmers are aptamers developed by SomaLogic.
• the C5 inhibitor is SSL7.
• SSL7 is a bacterial protein toxin described in Laursen et al. Proc. Natl. Acad. Sci. U.S.A., 107(8):3681-6.
• the C5 inhibitor is MEDI7814.
• MEDI7814 is a monoclonal antibody developed by Medlmmune.
• the C5 inhibitor is aurin tricarboxylic acid. In another embodiment, the C5 inhibitor is an aurin tricaiboxylic acid derivative. These aurin derivatives were developed by Aurin Biotech and are further described in U.S. Patent Appl. Pub. No. 2013/003592).
• the C5 inhibitor is RG6107/SKY59.
• RG6107/SKY59 is an anti-C5 recycling antibody developed by Roche Pharmaceuticals.
• the C5 inhibitor is Ravulizumab (ALXN1210). In another embodiment, the C5 inhibitor is ALXN5500. ALXN1210 and ALXN5500 are monoclonal antibodies developed by Alexion Pharmaceuticals.
• the C5 inhibitor is TT30.
• TT30 is a fusion protein developed by Alexion Pharmaceuticals.
• the C5 inhibitor is ABP959.
• ABP959 is an eculizamab biosimilar monoclonal antibody developed by Amgen.
• the C5 inhibtor is Anti-C5 siKNA.
• Anti-C5 siRNA was developed by Alnylam Pharmaceuticals.
• the C5 inhibitor is Erdigna ® .
• Erdigna ® is an antibody developed by Adienne Pharma.
• the C5 inhibitor is avacincaptad pegol/Zimura ® .
• Avacincaptad pegol is in aptamer developed by Opthotech.
• the C5 inhibitor is SOBI005.
• SOBI005 is a protein in developed by the Swedish Orphan Biovitrum.
• the C5 inhibitor is ISU305.
• ISU305 is a monoclonal antibody developed by ISU ABXIS.
• the C5 inhibitor is REGN3918.
• REGN3918 is a monoclonal antibody developed by Regeneron.
• a morphic form or composition as described herein may be provided in combination with ABP959, a monoclonal antibody directed to the complement factor C5 and manufactured and marketed by Amgen.
• a morphic form or composition or composition as described herein may be provided in combination with BOW080, a monoclonal antibody directed to the complement factor C5 and manufactured and marketed by Epirus Biopharmaceuticals.
• a morphic form or composition or composition as described herein may be provided in combination with SB 12, a monoclonal antibody directed to the complement factor C5 and manufactured and marketed by Samsung Bioepis.
• the factor D mediated disorder is PNH.
• the C3 inhibitor is a small molecule.
• the C3 inhibitor is a polyclonal antibody targeting C3.
• the C3 inhibitor is a monoclonal antibody targeting C3.
• the C3 inhibitor is an aptamer.
• C3 inhibitors are known in the art.
• a a morphic form or composition of the present invention is administered in combination or alternation with compstatin and/or a compstatin analog.
• Compstatin and compastin analogs are known and are found to be useful inhibitors of C3, see U.S. Patent Nos. 9,056,076; 8,168,584; 9,421,240; 9,291,622; 8,580,735; 9371365; 9,169,307; 8,946,145; 7,989,589; 7,888,323; 6,319,897; and US Patent Appl. Pub. Nos.
• the compstatin analog having the amino acid sequence ICWQDWGHHCRT (SEQ. ID. NO. 1).
• the C3 inhibitor is a compstatin analog.
• the compstatin analog is 4(lMeW)/APL-l of the sequence Ac-ICV(l- mW)QDWGAHRCT(SEQ. ID. NO. 2), wherein Ac is acetyl and 1-mW is 1-methyltryptophan.
• the compstatin analog is Cp40/AMY-101, which has an amino acid sequence yICV(lmW)QDW-Sar-AHRC-mI (SEQ. ID. NO. 3), wherein y is D-tyrosine, lmW is 1-methyltryptophan, Sar is sarcosine, and ml is /V-methylisoleucine.
• the compstatin analog is PEG-Cp40, having the amino acid sequence PEG-yICV(lmW)QDW- Sar-AHRC-ml (SEQ. ID. NO.
• the compstatin analog is 4(lMeW)POT-4. 4(lMeW)POT-4 was developed by Potentia. In yet another embodiment, the compstatin analog is AMY-201. AMY-201 was developed by Amyndas Pharmaceuticals.
• a a morphic form or composition of the present invention can be combined with C3 inhibitors that include, but are not limited to: HI 7 (monoclonal antibody, EluSys Therapeutics, Pine Brook, NJ); mirococept (CRl-based protein); sCRl (CRl-based protein, Celldex, Hampton, NJ); TT32 (CR-1 based protein, Alexion Pharmaceuticals, New Haven, CT); HC-1496 (recombinant peptide); CB 2782 (enzyme, Catalyst Biosciences, South San Francisco, CA); APL-2 (pegylated synthetic cyclic peptide, Apellis Pharmaceuticals, Crestwood, KY); or combinations thereof.
• the C3 inhibitor is H17.
• H17 is a humanized monoclonal antibody in development by EluSys Therapeutics.
• HI 7 is described in Paixao-Cavalcante et al. J. Immimol. 2014, 192(10):4844-4851.
• the C3 inhibitor is mirococept.
• Mirococept is a CR1 -based protein developed by Mlazyme Pharmaceuticals.
• the C3 inhibitor is sCRl.
• sCRl is a soluble form of the CR1 protein developed by Celldex.
• the C3 inhibitor is TT32.
• TT32 is a CR-1 based protein developed by Alexion Pharmaceuticals.
• the C3 inhibitor is HC-1496.
• HC-1496 is a recombinant peptide developed by InCode.
• the C3 inhibitor is CB 2782.
• CB 2782 is novel protease derived from human membrane type serine protease 1 (MTSP-1) that was developed by Catalyst Biosciences.
• the C3 inhibitor is APL-2.
• APL-2 is a pegylated version of APL-1 developed by Apellis Pharmaceuticals.
• CFB inhibitors are known in the art.
• a a morphic form or composition of the present invention can be combined with CFB inhibitors that include, but are not limited to: anti-FB SiRNA (Alnylam Pharmaceuticals, Cambridge, MA); TA106 (monoclonal antibody, Alexion Pharmaceuticals, New Haven, CT); LNP023 (small molecule, Novartis, Basel, Switzerland); SOMAmers (aptamers, SomaLogic, Boulder, CO); bikaciomab (Novelmed Therapeutics, Cleveland, OH); complin (see, Kadam et al., J. Immimol.
• CFB inhibitors include, but are not limited to: anti-FB SiRNA (Alnylam Pharmaceuticals, Cambridge, MA); TA106 (monoclonal antibody, Alexion Pharmaceuticals, New Haven, CT); LNP023 (small molecule, Novartis, Basel, Switzerland); SOMAmers (aptamers, SomaLogic, Boulder, CO); bikaciomab (Novelmed Therapeutics, Cleveland,
• CFB inhibitors that can be combined with a compound of the present invention include those disclosed in PCT/US17/39587.
• CFB inhibitors that can be combined with a compound of the present invention as described herein include those disclosed in PCT/US17/014458.
• CFB inhibitors that can be combined with a compound of the present invention as described herein include those disclosed in U.S. Patent Appl. Pub. No. 2016/0024079; . PCT Int. Appl. WO 2013/192345; PCT Int. Appl. WO 2013/164802; PCT Int. Appl. WO 2015/066241; PCT Int. Appl. WO 2015/009616 (assigned to
• the CFB inhibitor is a small molecule. In another embodiment the CFB inhibitor is a polyclonal antibody targeting CFB. In another embodiment the CFB inhibitor is a monoclonal antibody targeting CFB. In yet another embodiment the CFB inhibitor is an aptamer.
• the CFB inhibitor is 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-N-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
• the CFB inhibitor is anti-FB siRNA.
• Anti-FB siRNA was developed by Alnylam Pharmaceuticals.
• the CFB inhibitor is TA106.
• TA106 is a monoclonal antibody developed by Alexion Pharmaceuticals.
• the CFB inhibitor is LNP023.
• LNP023 is a small molecule inhibitor of CFB developed by Novartis.
• the CFB inhibitor is complin.
• Complin is a peptide inhibitor that is described in Kadam et al. J. Immunol. 2010 184(12):7116-24.
• the CFB inhibitor is Ionis-FB-Lax.
• Ionis-FB-Lax is a ligand conjugated antisense drug developed by Ionis Pharmaceuticals.
• pan-inhibitor of complement components are known in the art.
• the inhibitor is FUT-175.
• a method for treating a host in need thereof that comprises administering an effective amount of a prophylactic anti-bacterial vaccine prior to administration of a morphic form or composition for any of the disorders described herein.
• a method is provided for treating a host in need thereof that comprises administering an effective amount of a prophylactic anti-bacterial drug, such as a pharmaceutical drug, prior to administration of a morphic form or composition for any of the disorders described herein.
• a method is provided for treating a host in need thereof that comprises administering an effective amount of an antibacterial vaccine after administration of a morphic form or composition for any of the disorders described herein.
• a method for treating a host in need thereof comprises administering an effective amount of an anti-bacterial drug, such as a pharmaceutical drug, after administration of a morphic form or composition for any of the disorders described herein.
• the disorder is PNH, C3G, or aHUS.
• the host has received an organ or other tissue or biological fluid transplant.
• the host is also administered eculizumab.
• a morphic form or composition as described herein is administered to a host concomitantly to a subject following the prophylactic administration of a vaccine against a bacterial infection.
• the complement mediated disorder is PNH, C3G, or aHUS.
• the subject has received an organ or other tissue or biological fluid transplant.
• the subject is also administered eculizumab.
• a morphic form or composition as described herein is administered to a subject concomitantly with the prophylactic administration of a vaccine against a bacterial infection.
• the complement mediated disorder is PNH, C3G, or aHUS.
• the subject has received an organ or other tissue or biological fluid transplant.
• the subject is also administered eculizumab.
• a morphic form or composition as described herein is administered to a subject and, during the administration period of the morphic form, a vaccine against a bacterial infection is administered to the subject.
• the complement mediated disorder is PNH, C3G, or aHUS.
• the subject has received an organ or other tissue or biological fluid transplant.
• the subject is also administered eculizumab.
• the subject is administered a morphic form or composition as described herein in combination with an antibiotic compound for the duration of Factor D inhibitor administration.
• the complement mediated disorder is PNH, C3G, or aHUS.
• the subject has received an organ or other tissue or biological fluid transplant.
• the subject is also administered eculizumab.
• a morphic form or composition as described herein is administered to a subject following the prophylactic administration of a vaccine against a bacterial infection, and in combination with an antibiotic compound for the duration of Factor D inhibitor administration.
• the complement mediated disorder is PNH or aHUS.
• the subject has received an organ or other tissue or biological fluid transplant.
• the subject is also administered eculizumab.
• the subject, prior to receiving a morphic form or composition as described herein is vaccinated against a bacterial infection caused by the bacterium Neisseria meningitidis.
• the subject is vaccinated against a bacterial infection caused by the bacterium Haemophilus influenzae.
• the Haemophilus influenzae is Haemophilus influenzae serotype B (Hib).
• the subject is vaccinated against a bacterial infection caused by Streptococcus pneumoniae.
• the subject is vaccinated against a bacterial infection caused by the bacterium Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae, or a combination of one or more of Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae.
• the subject is vaccinated against a bacterial infection caused by the bacterium Nisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae.
• the subject is vaccinated against a bacterial infection caused by a bacterium selected from a Gram-negative bacterium. In one embodiment, the subject is vaccinated against a bacterial infection caused by a bacterium selected from a Gram-positive bacterium.
• the subject is vaccinated against a bacterial infection caused by the bacterium Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneunemoniae, or a combination of one or more of Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae, and one or more of, but not limited to, Bacillus anthracis, Bordetella pertussis, Clostridium tetani, Coiynebacterium diphtheria, Coxiella burnetii, Mycobacterium tuberculosis, Salmonella typhi, Vibrio cholerae, Anaplasma phagocytophilum, Ehrlichia ewingii, Ehrlichia chaffeensis, Ehrlichia canis, Neorickettsia sennetsu, Mycobacterium leprae, Borrelia burgdorferi, Borrelia mayonii, Borreli
• the subject is vaccinated with one or more vaccines selected from, but not limited to, typhoid vaccine, live (Vivotif Bema Vaccine, PaxVax), typhoid Vi polysaccharide vaccine (Typhim Vi, Sanofi), pneumococcal 23 -polyvalent vaccine, PC VI 3 (Pneumovax 23, Merck), pneumococcal 7-valent vaccine, PCV7 (Prevnar, Pfizer), pneumococcal 13-valent vaccine, PCV13 (Prevnar 13, Pfizer), haemophilus b conjugate (prp-t) vaccine (ActHIB, Sanofi; Hibrix, GSK), haemophilus b conjugate (hboc) vaccine (HibTITER, Neuron Biotech), haemophilus b conjugate (prp-omp) vaccine (PedvaxHIB, Merck), haemophilus b conjugate (prp-t) vaccine/
• a subject receiving a compound of the present invention to treat a disorder is prophylactically administered an antibiotic compound in addition to a Factor D inhibitor described herein.
• the subject is administered an antibiotic compound for the duration of administration of the active compound to reduce the development of a bacterial infection.
• Antibiotic compounds for concomitant administration with a Factor D inhibitor described herein can be any antibiotic useful in preventing or reducing the effect of a bacterial infection.
• Antibiotics are well known in the art and include, but are not limited to, amikacin (Amikin), gentamicin (Garamycin), kanamycin (Kantrex), neomycin (Neo-Fradin), netilmicin (Netromycin), tobramycin (Nebcin), paromomycin (Humatin), streptomycin, spectinomycin (Trobicin), geldanamycin, herbimycin, rifaximin (Xifaxan), loracarbef (Lorabid), ertapenem (Invanz), doripenem (Doribax), imipenem/cilastatin (Primaxin), meropenem
• the subject is administered a prophylactic antibiotic selected from cephalosporin, for example, ceftriaxone or cefotaxime, ampicillin-sulbactam, Penicillin G, ampicillin, chloramphenicol, fluoroquinolone, aztreonam, levofloxacin, moxifloxacin, gemifloxacin, vancomycin, clindamycin, cefazolin, azithromycin, meropenem, ceftaroline, tigecycline, clarithromycin, moxifloxacin, trimethoprim/sulfamethoxazole, cefuroxime, axetil, ciprofloxacin, rifampin, minocycline, spiramycin, and cefixime, or a combination of two or more thereof.
• cephalosporin for example, ceftriaxone or cefotaxime, ampicillin-sulbactam, Penicillin G, ampicillin, chloramphenicol, fluoro
• Compound 1 for example, can be synthesized by the procedure disclosed in PCT Application WO2015130795 and Compound 2, for example, can be synthesized by the procedure disclosed in PCT Application WO2017035353.
• An alternative synthesis of Compound 1 is shown below in Scheme 1 and an alternative synthesis of Compound 2 is shown below in Schemes 2-7.
• intermediate 9 was synthesized from intermediate 6 via a one-pot palladium-catalyzed Miyaura borylation/Suzuki cross-coupling reaction.
• 4-Bromo-2- methylpyrimidine (7) was reacted with bis(pinacolato)diboron to afford boronate ester 8.
• intermediate 6 underwent a Suzuki reaction with boronate ester 8 to generate the coupled product, intermediate 9.
• intermediate 12 was synthesized from intermediate 11 using a one-pot Miyaura borylation/Suzuki coupling.
• This one-pot Miyaura borylation/Suzuki coupling can be conducted between bromine- containing reagents, chloride-containing reagents, iodide-containing reagents, organotriflate- containing reagents, or any combination thereof.
• the reaction can also be conducted with alternative Suzuki catalysts including, but not limited to, XPhos-Pd-Gl, XPhos-Pd-G2, XPhos, or CataCXium A as defined in Molander et al.
• the reaction is conducted with Suzuki catalysts XPhos-Pd-Gl and XPhos or XPhos-Pd-G2 and XPhos.
• the borylation reagent can also be selected from, but not limited to, pinacolborane or bis-boronic acid. Examples
• Step 1 Synthesis of terf-Butyl (2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4- fluoropyrrolidine-l-carboxylate (3): A'-Boc-troros ⁇ -Fluoro-L-proline (50.8 kg) was added to DCM (1000 L) in a glass-lined reactor under an atmosphere of nitrogen. The reaction mixture was cooled to 0 ⁇ 5°C and N-methylimidazole (44.7 kg) was added while maintaining the temperature at 0 ⁇ 5°C.
• Methanesulfonyl chloride (29.97kg) was slowly added to the reaction mixture followed by the addition of 2-amino-6-bromopyridine (2).
• the reaction temperature was warmed to room temperature and stirred for 12h.
• the reaction was monitored by HPLC.
• the aqueous layer was once more extracted with DCM (1000 L).
• the combined DCM layer was washed in succession with dilute HC1, aqueous NaHCCb and brine.
• Step 2 Synthesis of (2S,4R)-N-(6-Bromopyridin-2-yl)-4-fluoropyrrolidine-2- carboxamide (4): To a solution 4M HCl/Dioxane (168 kg) was added intermediate 3 (40 kg) at 25 ⁇ 5 °C under an atmosphere of nitrogen and the reaction was stirred for lh. The reaction was monitored by HPLC and after completion, the reaction was diluted with DCM (800 L) and washed with aqueous NaHCCb. The DCM layer was separated and concentrated.
• Step 3 Synthesis of tert-Butyl 2-(3-acetyl-5-bromo-lH-indazol-l-yl)acetate (6): l-(5- Bromo- lH-indazol-yl)ethan- 1 -one (5, 30 kg) was added to a reactor containing DMF (210 L) under an atmosphere of nitrogen followed by potassium carbonate (4.05 kg). Tert-butyl bromoacetate (3.42 kg) was added to the reaction mixture with stirring and maintaining the temperature at 30 ⁇ 10 °C. After addition was complete, the reaction mixture was heated at 50 ⁇ 5 °C for lh. After the reaction was complete the reaction mixture was cooled to 25 ⁇ 5 °C and diluted with water (630 L). The precipitated solid was filtered, washed with water (90 L) and dried. Yield, 43.13 kg, 97.13%.
• Step 4 Synthesis of tert-Butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-lH-indazol-l- yl)acetate (9): Bispinnacolato diboron (14.67kg) was added to a solution of 4-bromo-2- methylpyrimidine (7, 10 kg) in dioxane (206kg) under an atmosphere of nitrogen followed by the addition of potassium acetate (17kg). The reaction mixture was degassed using nitrogen. Pd(dppf)Ck (0.94 kg) was added and the reaction mixture heated to 90 ⁇ 5°C until the pyrimidine was consumed.
• reaction mixture was cooled to 25 ⁇ 5°C and intermediate 6 (16.33kg) was added followed by potassium carbonate (20.7kg) and water (16.33 kg) and the reaction was degassed using nitrogen. The reaction was again heated to 90 ⁇ 5°C until completion.
• the reaction mixture was cooled to 25 ⁇ 5°C and diluted with ethyl acetate (269kg) and water (150 kg) maintaining the temp at 10 ⁇ 5°C.
• Activated charcoal (1kg) was added to the mixture with stirring and then filtered through a bed of celite. The ethyl acetate layer was separated, washed with 5% aqueous sodium chloride followed by 5% L-Cysteine solution to remove palladium related impurities. The ethyl acetate layer was evaporated to dryness.
• the product (9) was isolated from MTBE/heptane. Yield, 11.8 kg, 56%.
• Step 5 Synthesis of 2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-lH-mdazol-l-yl)acetic acid (10): To a stirred solution of intermediate 9 (50 kg) in DCM (465 kg) at 15 ⁇ 5°C was added TFA (374.5 kg) while maintaining the said temperature. The reaction was warmed to 35 ⁇ 5°C and stirring continued until completion of the reaction. DCM and TFA were distilled off under reduced pressure. The residue was dissolved in DCM (kg) and stirred with aqueous sodium bicarbonate. The biphasic mixture was acidified with concentrated HC1 and the pH was adjusted to 2-3. The precipitated solid was filtered, washed with water and dried. Yield, 42.4 kg, quantitative.
• Step 6 Synthesis of Compound 1: To a solution of intermediate 9 (42 kg) in DMF (277 kg) was added intermediate 4 (38.7 kg) and the reaction was cooled to 10 ⁇ 5°C. Coupling agent TBTU (56.7 kg) was added to the reaction mixture followed by the addition of DIPEA (86.5 kg) while maintaining the reaction temperature at 10 ⁇ 5°C. The reaction was warmed to 25 ⁇ +5°C and stirred until complete. The reaction mixture was diluted with ethyl acetate (1344 kg) and washed with water twice. (The reaction may be washed with aq.
• Amorphous Compound 1 was analyzed by FT-Raman spectroscopy, differential scanning calorimetry, (DSC), thermogravimetric analysis (TGA), TGA with IR off-gas detection (TGA- IR), polarized light microscopy (PLM), powder X-ray diffraction (PXRD), dynamic vapor sorption (DVS), and modulated DSC.
• the selected physicochemical data of amorphous Compound 1 is presented in Figure 1A, Figure IB, Figure 1C, Figure ID, Figure IE, and Figure IF.
• the figures indicate that the material is a light brown powder determined to be amorphous by PXRD (Figure 1C) and PLM ( Figure ID).
• the DSC data shows low energy broad endotherms at 37.3°C and 113.4°C (Figure IB).
• TGA-IR data ( Figure IB) indicates that the material contains residual water (2.0%) and DCM (1.8%).
• DVS analysis conducted on the amorphous form indicates 4.0% water uptake from 0-90%RH ( Figure IE).
• the sample remained amorphous after the DVS experiment by PXRD. In addition, no visual change to the physical appearance was observed.
• An estimated glass transition temperature of 117.8°C was observed by mDSC ( Figure
• the solubility of amorphous Compound 1 was estimated in 14 solvents to facilitate the solvent selection for the crystallization study.
• the solubility of Compound 1 was visually estimated at room temperature (RT; ⁇ 23 °C) by dosing small aliquots of solvent into a fixed amount of solid ( ⁇ 10 mg) until the dissolution point or a maximum volume (1.7 mL) was reached.
• the crystallization study involved a total of 24 solvent systems.
• the solubility data from Example 2 was utilized to create a diverse set of neat and binary solvent mixtures to target a solubility of 5-100 mg/mL.
• the composition of binary mixtures was varied during the course of crystallization to achieve various levels of supersaturation to encourage crystallization.
• aqueous mixtures were employed to probe for the formation of hydrates.
• Samples were prepared by adding ⁇ 15mg of amorphous Compound 1 to 2mL vials containing a tumble-stir disk. Solvents were added with volumes ranging from 250pL to 500pL (experiment dependent).
• PLM Polarized-Light microscopy
• PXRD diffractograms were acquired using PANalytical X’Pert Pro diffractometer on Si zero-background wafers. All diffractograms were collected using a Cu Ka (45 kV/40 mA) radiation and a step size of 0.02° 2Q and XceleratorTM RIMS (Real Time Multi-Strip) detector. Nickel filter was used to reduce unwanted radiation, unless noted otherwise. Configuration on the incidental beam side: fixed divergence slit (1 ⁇ 4 deg), 0.04 rad seller slits, anti-scatter slit (1 ⁇ 4 deg), and 10mm beam mask. Configuration on the diffracted beam side: fixed divergence slit (1 ⁇ 4 deg) and 0.04 rad seller slit.
• Raman spectra were collected with a Nicolet NXR9650 or NXR 960 spectrometer (Thermo Electron) equipped with 1064 ran Nd:YV04 excitation laser, InGaAs and liquid-N2 cooled Ge detectors, and a MicroStage. All spectra were acquired at 4 cm-1 resolution, 64-128 scans, using Happ-Genzel apodization function and 2-level zero-filling.
• DSC was conducted with a TA Instruments Q100 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL/min N2 purge. DSC thermograms were obtained at 15oC/min in crimped A1 pans.
• TGA thermograms were obtained with a TA Instruments Q500 thermogravimetric analyzer under 40 mL/min N2 purge at 15oC/min in Pt or A1 pans.
• TGA-IR was conducted with a TA Instruments Q5000 thermogravimetric analyzer interfaced to a Nicolet 6700 FT-IR spectrometer (Thermo Electron) equipped with an external TGA-IR module with a gas flow cell and DTGS detector.
• TGA was conducted with 60 mL/min N2 flow and heating rate of 15oC/min in Pt or A1 pans. IR spectra were collected at 4 cm-1 resolution and 32 scans at each time point.
• Form A is a crystal form precipitated from a solution in PEG300 during an excipient solubility study of Compound 1.
• Form A was not observed during the crystallization study of Example 3, but the crystal form was characterized by PXRD, FT-Raman, PLM, DSC, and TGA- IR.
• the physicochemical data of Form A are presented in Figure 3A, Figure 3B, Figure 3C and Figure 3D.
• Form I is crystalline by PXRD ( Figure 3C) and PLM ( Figure 3D).
• DSC shows a low energy broad endotherm at 68.6°C and 2.4% (0.8 eq.) weight loss from water is observed from 25°C-150°C by TGA-IR ( Figure 3B).
• Compound 1 Form II (Monohydrate)
• Form P is a monohydrate form observed in the crystallization study of Example 3.
• a lower crystallinity sample of Form II was also found in an evaporation experiment from ethanol.
• Form P was prepared by adding amorphous Compound 1 (82.1mg) to a 4-mL vial containing a tumble-stir disk. Heptane (lmL) and ethanol (lmL) were added along with 2mg of Form P seeds (CS-19). The suspension was stirred while cycling the temperature between 40 °C and 5°C for 3 days. The suspension was filtered and then dried under vacuum for 20 minutes.
• Form P is crystalline by PLM (Figure 4D) and PXRD ( Figure 4C) and contains 2.7% bound water ( ⁇ 0.9eq) which is released with a broad endotherm in the DSC from 40-125°C ( Figure 4B). A final melting endotherm is observed at 155.3°C. Heating Form P past the dehydration endotherm and returning to room temperature does not change the crystal-form by PXRD or water content by TGA, indicating it is a reversible hydrate. Furthermore, DVS analysis conducted on the material ( Figure 4E) indicates the hydrate exists with ⁇ 2.7-4.0% water and shows a critical RH step at 30%RH which supports the data indicating that Form P reversibly hydrates.
• Form PI is a crystal form observed from the residual solids of a sample of Form P stirred in water for 4 days. Form PI was also observed during relative stability experiments (Example 5) with higher crystallinity than the batch observed from the residual solids of a sample of Form II ( Figure 5).
• Form IP is crystalline by PXRD ( Figure 6A) and contains 4.0% bound water ( ⁇ 1.3eq) which is released with a broad endotherm in the DSC from 40-125°C ( Figure 6B). A final endotherm is observed at 141.0°C. Drying Form PI at 70°C under vacuum for 1 hour did not change the crystal-form
• Form IV is a hydrated form observed in one sample that was filtered from PEG400.
• Form IV is crystalline by PXRD ( Figure 7A) and contains 7.2% bound water ( ⁇ 2.5eq) which is released with an endotherm in the DSC at 76.8°C ( Figure 7B).
• Form IV is physically stable in sealed vial for at least 10 days by PXRD.
• Form V is a hydrated form observed during a scale-up attempt of Form IV.
• Form V was prepared by adding amorphous Compound 1 (30mg) to methanol/ 1 Ovol%water (500uL) at 25°C and stirring for 10 minutes. A clarifying filtration was performed into clean HPLC vial. Seeds of Form IV (lmg) were added and stirred at 25°C. Clouding occurred after a few minutes. Solids were isolated after 30 minutes of stirring at 25°C (thick slurry).
• Form V is crystalline by PXRD ( Figure 8A) and contains 11.1% water ( ⁇ 4.0eq) and a trace amount of methanol. DSC shows a broad endotherm at 62.3°C ( Figure 8B). The thermal analysis data does not definitively indicate whether the water and methanol are bound or residual. Further studies on Form V are required (e.g. drying).
• Form VI is a mixed water/acetone solvate form observed during a scale-up attempt of
• Form VI was prepared by adding amorphous Compound 1 (30mg) to acetone: water (3:2, 500uL) at 25°C and stirring for 10 minutes. A clarifying filtration was performed into clean HPLC vial. Seeds of Form IV (lmg) were added and stirred at 25°C. Clouding occurred after a few minutes.
• Form VI is crystalline by PXRD ( Figure 9A) and contains 13.8% bound water and acetone which is released with a broad endotherm in the DSC at 44.1°C ( Figure 9B).
• the PXRD pattern of Form VI is similar to Form V as shown in Figure 10 A. After sitting overnight on a PXRD holder, Form VI closely resembles Form V as shown in Figure 10B.
• Compound 1 Form VII is crystalline by PXRD ( Figure 9A) and contains 13.8% bound water and acetone which is released with a broad endotherm in the DSC at 44.1°C ( Figure 9B).
• the PXRD pattern of Form VI is similar to Form V as shown in Figure 10 A. After sitting overnight on a PXRD holder, Form VI closely resembles Form V as shown in Figure 10B.
• Compound 1 Form VII Compound 1 Form VII
• Form VH is a mixed water/IPA solvate form observed from a sample submitted for single crystal analysis.
• the physicochemical data of Form VII is presented in Figure 11 A and Figure 1 IB.
• Form VII is crystalline by PXRD ( Figure 11 A) and contains 14.0% water and IPA by TGA-IR ( Figure 1 IB).
• the PXRD pattern of Form VII is similar to Form VI as shown in Figure 12 indicating that the material is likely a mixed solvate containing water and IPA.
• Step 1A Suzuki coupling: Bromo methyl pyrimidine (11, 10 Kg, 1 eq) was dissolved in 1,4-dioxane (200 Kg, 20 vol.) and bispinacolato diborane (14.7 Kg, leq) and potassium acetate (17 Kg, 3 eq) were added. The reaction was degasified for 15 minutes with N2 for 30 minutes and Pd(dppf)Ch (1.4 Kg, 0.03 eq) was added. The reaction was again degasified for 15 minutes and stirred for 2 hours at 95 ⁇ 5° C.
• the reaction was then cooled to 25 ⁇ 5°C and charged with bromo-7-methyl- lH-indazole (7, 9.15 Kg, 0.8 eq), K2CO3 (23.9 Kg, 3 eq).
• the reaction was degasified for 15 minutes and stirred for 2 hours at 95 ⁇ 5° C.
• the reaction mass was cooled to 25 ⁇ 5° C, diluted with 10% methanol in DCM (20 vol), charged with charcoal (0.1 w/w), stirred for 30 minutes, and filtered through a celite bed. The filtrate layers were separated and the aqueous layer was extracted with 10% methanol in DCM (10 vol.).
• Step 2A Iodination: Intermediate 12 (11.5 Kg, 1 eq) was dissolved in THF (95.7 Kg, 10 vol) and heated to 60 ⁇ 5°C to obtain a clear solution. The mass was cooled to 0-5°C and iodine (19.55 Kg, 1.5) was added followed by potassium tert-butoxide (14.35 Kg, 2.5 eq) lot-wise and the reaction mass was stirred for 1 hour at room temperature. The reaction mass was quenched with 10% sodium thiosulphate solution (15 vol) and 10 vol water was added into the reaction mass at room temperature. The reaction was stirred for 8 hours and the resulting solid was filtered to afford intermediate 13 (Yield: 13.41 Kg. yield 74.7 %).
• Step 3A N- Acetylation: A reaction flask was charged with DMF (174.3 Kg, 14 vol) and intermediate 13 (13.2 Kg, leq) and the reaction was heated to 55°C to 60°C to obtain a clear solution. The reaction was cooled to 25 °C and ethoxyvinyl stannate (61.25 Kg, 4.5 eq) was added under nitrogen. The reaction was then degasified for 10 -15 minutes under a N2 atmosphere before Pd(dppf)ChDCM (3.07 Kg, 0.02 eq) was added and the reaction was stirred for 2 hours at 80 °C. The reaction mass was quenched with 3M HC1 (50 w/w) and stirred for 2 hours.
• 3M HC1 50 w/w
• Step 4A N-Alkylation: Intermediate 14 (6.25 Kg, leq) was taken up in DMF (58.3 Kg, 7 vol) and K2CO3 (9.61 Kg, 3 eq) was added at 25 ⁇ 5°C. Tert-butyl bromoacetate (5.0 Kg, 1.2 eq) was added slowly and the reaction mass was stirred for 2 hours at 50 ⁇ 5°C. The reaction mass was cooled to 15 ⁇ 5°C, quenched with water (22 vol.), and stirred for 3 hours at 25 ⁇ 5°C. The resulting solid was filtered and washed with water (5 vol.).
• Step 5A Ester Hydrolysis: A reaction flask was charged with DCM (93.1 Kg, 10 vol) and intermediate 15 (7 Kg, 1 eq). The reaction was cooled to 15 ⁇ 5°C and TFA (52.1 Kg, 5 vol) was slowly added at 15 ⁇ 5°C. The temperature was raised to 35 ⁇ 5°C and the reaction was stirred for 2 hours at 35 ⁇ 5°C. DCM and TFA removed under reduced pressure and the resulting crude material was dissolved in DCM (10 vol.). 10% NaHCOs solution (20 vol.) was slowly added to adjust the pH to 7.5 - 8.
• Step IB To a solution of BOC-pyro glutamic acid methyl ester (17, 95 Kg, leq,) in 2- dimethoxy ethane (1 vol), Bredereck reagent (95 Kg, 1.05 eq,) was added. The mass was stirred for 4 hours at 75° ⁇ 5°C. After the completion, the mass was cooled to 25 ⁇ 5°C and n-heptane (5 vol) was added. The mass was further cooled mass to 0 ⁇ 5°C and stirred for 2-3 hours. The resulting solid was filtered and washed with n-heptane. The crude material (18) was used in the next step.
• Step 2B Crude material (18) was dissolved in IPA (5 vol) and Pd/C (0.1 w/w, 9.5 Kg) was added lot-wise. The reaction was stirred for 14 hours at 55 ⁇ 5°C. After completion, the reaction was cooled to 25 ⁇ 5°C, filtered and washed with IPA. The filtered layer was concentrated, n-heptane (3 vol) was added, and the solution was cooled to 0 ⁇ 5°C and stirred for 1 hour. The resulting solid was filtered and dried to afford intermediate 19 (Yield: 87.2 Kg; 86.8
• Step 3B To a solution of intermediate 19 (leq, 75 Kg) in toluene (10 vol), lithium triethylborohydride (abt. 20% in THF) (123 Kg) was added at -60 ⁇ 5°C and the reaction was stirred for 1 hour. After completion, methanol (2.5 vol) was added followed by water (10 vol). The aqueous layer was extracted with ethyl acetate (10 vol) and the combined organic layers were washed with brine solution and concentrated to afford 80 Kg of crude 20.
• lithium triethylborohydride abt. 20% in THF
• Step 4B Intermediate 20 was dissolved in toluene (10 vol) and 2,6-lutidine (1.5 eq, 46.6 Kg) was added at 0 ⁇ 5°C. Trifluoroacetic anhydride (1 eq, 61.5 Kg) was added at 0 ⁇ 5°C and the reaction mixture was heated to 50 ⁇ 5 °C and stirred before the temperature was raised to 25 ⁇ 5°C and quenched with water (10 vol). The aqueous layer was extracted with ethyl acetate (10 vol) and the combined organic layers were washed with brine solution and concentrated. Crude material was purified by column chromatography using ethyl acetate/n-heptane to afford 53.8 Kg of crude 21.
• Step SB Intermediate 21 was dissolved in THF:ethanol (1:1.5, 25 vol) and sodium borohydride (5 eq, 23.5 Kg + 0.314 Kg ) was added lot-wise followed by lithium chloride (3 eq, 26.5 Kg + 0.314 Kg) lot-wise at 25 ⁇ 5°C. The reaction was stirred for 2 hours at 25 ⁇ 5°C. After completion, the mass was cooled to 0 ⁇ 5°C, quenched with water (10 vol), and concentrated. The mass was further diluted with water (5 vol) and ethyl acetate was added. The mass was filtered through a celite bed and the aqueous layer was washed with ethyl acetate (10 vol x 1). The combined organic layers were washed with water (10 vol) and brine solution (5 vol), dried over sodium sulphate, filtered and concentrated to afford intermediate 22.
• sodium borohydride 5 eq, 23.5 Kg + 0.314 Kg
• lithium chloride 3 eq, 26.5 Kg +
• Step 6B Intermediate 22 was dissolved in DCM (10 vol) and the reaction was cooled to 0 ⁇ 5°C.
• DMAP 0.1 eq, 2.24 Kg
• TEA 2.5 eq, 65 Kg
• benzoyl chloride (1.05 eq, 37.4 Kg) were added and the temperature was raised to 25 ⁇ 5°C and stirred for 2 hours.
• DCM 10 vol
• water 10 vol
• the organic material was washed with water and concentrated.
• the crude material was purified by column chromatography using ethyl acetate and n-heptane to afford intermediate 23 (Yield: 63.2 Kg; overall yield 51 %)
• Step 7B Intermediate 23 (1 eq, 62 Kg) was dissolved in toluene (20 vol) and the mass was cooled to -25 to -30°C. 1.5M Diethyl zinc in toluene (2.5 eq, 262 Kg) was added and the reaction was stirred for 30 minutes at 25 to -30°C. Chloroiodomethane (6 eq, 180 Kg) was added and the reaction was stirred for an additional 30 minutes at 25 to -30°C. The reaction mass temperature was raised to -2 ⁇ 5°C and stirred for 4 hours.
• reaction mass was cooled to -10 ⁇ 5°C, quenched with 10% sodium bicarbonate solution (10 vol), stirred for 10- 15 minutes at 25 ⁇ 5°C, filtered, and washed with ethyl acetate. The organic layer was washed with brine and concentrated to afford intermediate 24.
• Step 8B Intermediate 24 was dissolved in methanol and the reaction was cooled to 0 ⁇ 5°C. Sodium methoxide (1.1 eq, 38.5 Kg) solution was added and the reaction was stirred at 25 ⁇ 5°C for 2 hours. After completion, the reaction was cooled to 5 ⁇ 5°C, quenched with water (10 vol) and stirred for 8 hours. The methanol was concentrated and the aqueous layer was extracted with ethyl acetate (10x2). The combined organic layers were washed with brine solution and concentrated to afford intermediate 25 (Yield: 34.9 Kg; overall yield 81%)
• Step 9B Intermediate 25 (1 eq, 34.9 Kg) was dissolved in acetonitrile (154 kg, 5vol) and monosodium phosphate in water solution (2.5 w/w in water, 87.25 Kg) and TEMPO ( 0.12 eq, 2.44 Kg) were added at 25 ⁇ 5°C.
• Sodium chlorite (2.9 eq, 36.65 Kg) in water and sodium hypo chloride solution (0.36 vol, 10.5 Kg) was added simultaneously at 35 °C or below and the reaction was stirred for 8 hours below 35°C. After completion, the reaction was cooled to 20 ⁇ 5°C and 20% sodium sulphite solution (4 w/w 69.8 Kg) was added.
• the combined organic layers were washed with purified water (20 w/w and with 10 w/w).
• Sodium thiosulfate (10 w/w, 140.0 Kg) was added to the aqueous layer and it was stirred for 10 minutes before sodium chloride (15 w/w, 150.0 Kg) was added and the solution was stirred for an additional 10 minutes.
• DCM (20 vol.) was then added and the resulting solution was stirred for 15 minutes. Following separation of the two phases, the aqueous layer was extracted with DCM (20 vol.). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and washed with DCM (3 vol .).
• the aqueous layer was extracted with DCM (15 vol.) and the organic layer was washed with the 30% K2CO3 solution (purified water 14 w/w, K2CO3 6.0 w/w, 84.0 Kg) and NaCl solution (purified water 9 w/w, NaCl 1.0 w/w, 14.0 Kg) at 25 ⁇ 5 °C.
• the organic layer was concentrated and the resulting solid was cooled to 25 ⁇ 5 °C before TFA (7.45 w/w, 104.3 Kg) was added.
• the reaction stirred for 6 hours at 65 ⁇ 5 °C.
• the reaction was then concentrated and co-evaporated with DCM (5 vol.).
• the resulting mass was cooled to 25 ⁇ 5 °C and DCM (10 vol.) and 20 % K2CO3 solution (purified water 9.6 w/w, K2CO36.0 w/w, 2.4 Kg) were added at 25 ⁇ 5 °C.
• the resulting solution was stirred for 10 minutes.
• the aqueous layer was extracted with DCM (10 vol.) and the resulting mass was concentrated and purified via column chromatography using n-heptane and ethyl acetate as the mobile phase.
• the cartridge- filtered product fractions were concentrated and co-evaporated with cartridge-filtered n-heptane (0.7 vol.).
• HC1 solution (4.07 w/w purified water, 4.72 w/w HCl) and the solution was stirred for 10 minutes before DCM (10 vol.) was added.
• the aqueous layer was extracted with DCM (5 vol.) and the organic layer was washed with 2.69 w/w of HCl solution.
• the aqueous layer was extracted with DCM and NaHCCb (6.1 w/w) was added to adjust the pH to 7-8 before DCM was added.
• the resulting aqueous layer was extracted with DCM (10 vol. x 3 times) and the combined organic layers were concentrated.
• Step ID (5S)-5-(Hydroxymethyl)pyrrolidin-2-one (34, 15 g, 130.285 mmol, 1 equiv.), triethylamine (65.918 g, 90.796 mL, 651.426 mmol, 5 equiv.) and 4-dimethylaminopyridine (0.796 g, 6.514 mmol, 0.05 equiv.) in dichloromethane (200 mL, 0.434 M, 20 Vols) was cooled to 5 °C and benzoyl chloride (21.977 g, 18.147 mL, 156.342 mmol, 1.2 equiv.) ws slowly added. The reaction was stirred for 3 hours at room temperature.
• Step 2D [(2S)-5-oxopyrrolidin-2-yl]methyl benzoate (23 g, 104.908 mmol, 1 equiv.), 4- dimethylaminopyridine (6.408 g, 52.454 mmol, 0.5 equiv.) in dichloromethane (230 mL, 0.456 M, 10 Vols) was cooled to 5 °C and di-tert-butyl dicarbonate (34.344 g, 36.152 mL, 157.362 mmol, 1.5 equiv.) was added. The reaction was stirred overnight at room temperature. The solvent was removed from the reaction mixture and heptane (100 mL) was added.
• Step 3D and 4D Brederek reagent was added twice to intermediate 35 (25g) to yield 28.4g (97%) of product that was subjected to hydrogenation conditions (overnight reaction in IPA at 50°C). This resulted in 11.6 g (87% yield) of intermediate 36 after chromatographic purification. The material was solid and can be crystallized if needed.
• Step 5D To a stirred solution of tert-butyl (5S)-5-[(benzoyloxy)methyl]-3-methyl-2- oxopyrrolidine-l-carboxylate (36, 5 g, 14.998 mmol, 1 equiv.) in tetrahydrofuran (75 mL, 0.2 M, 15 Vols) was added lithiumtriethylborohydride (1.748 g, 16.497 mL, 16.497 mmol, 1.1 equiv.) at -78 °C under argon. The reaction mixture was stirred at -78 °C for 20-30 minutes and then quenched with a saturated NaHCCh solution at -78 to -70 °C.
• the reaction mixture was warmed to -20°C 30% hydrogen peroxide (5.612 g, 5.055 mL, 49.492 mmol, 3.3 equiv.) was added before further warming up to 0°C over 15-20 minutes.
• the aqueous phase was extracted with AcOEt/saturated aqueous NaCl and the organic phase was washed with saturated aqueous NaCl.
• the aqueous layer was extracted again with CH2CI2 twice and all organic layers were combined and concentrated.
• Step 6D tert-butyl (5 S)-5-[(benzoyloxy)methyl]-2-hydroxy-3-methylpyrrolidine- 1 - carboxylate (5.03 g, 14.997 mmol, 1 equiv.) and p-toluenesulfonic acid monohydrate (0.029 g, 0.15 mmol, 0.01 equiv.) were heated in toluene (50.3 tnL, 0.298 M, 10 Vols) for 2 hours at 70°C The reaction was cooled, washed with saturated aqueous NaHCCh, dried and evaporated. The crude material was purified by chromatography over silica gel (10% EtO Ac/hexane) to afford 3.5g of olefin 23.
• Step IE Intermediate 31 (10 kg) and intermediate 30 (7.4 kg) were dissolved in DCM/pyridine and cooled to 0 ⁇ 5°C. Phosphorousoxy chloride (7 kg) was added to the mixture while maintaining the reaction temperature. After the reaction was complete, water was added carefully and the reaction was allowed to warm to room temperature. The aqueous layer was extracted with DCM and the combined DCM layers were washed with dilute HC1 and water, dried over anhydrous sodium sulfate and evaporated to dryness. Heptane was added and evaporated and the residue triturated with 5% ethylacetate/heptane. The solid was filtered and dried to afford intermediate 32 (Yield 11.4 kg).
• Step 2E Intermediate 32 (5 kg) was added to 4M HCl/dioxane (21kg) and the reaction was stirred at room temperature. After completion, the reaction was diluted with DCM and carefully washed with aqueous NaHCCh. The DCM layer was washed with water and evaporated to dryness. The product was crystallized from DCM/heptane to afford intermediate 33 (Yield 3.8 kg).
• Ambient temperature (RT) solvent/anti-solvent precipitation experiments were generally unsuccessful.
• a set of experiments utilizing tetrahydrofuran as the solvent and either water or heptane as the anti-solvent generated enough solids for characterization.
• HFIPA hexafluoroi sopropy 1 alcohol
• the solution discolored (yellow/ brown/ red).
• Either Form 1 or disordered Compound 2 was generated from these experiments.
• the vast majority of the other solvent combinations attempted produced solids free solutions. However, sonicating these solutions generated a number of solid materials. All the recovered solids from these soni cation experiments were Compound 2 Form 1.
• the disordered Compound 2 was subjected to water activity slurries in methanol at ambient temperature and Form 1 resulted.
• volume Reduction Saturated solutions of Compound 2 and a solvent/ solvent system of interest were prepared. The solutions were filtered and left open to ambient conditions. The volume reduction was halted prior to the sample drying completely, the samples capped and left at ambient temperature.
• Crash Precipitation A saturated solution of Compound 2 and a solvent of interest was prepared at elevated temperature. This solution was filtered directly into a vessel containing an anti-solvent at ambient temperature. The samples were monitored for immediate generation of solids.
• Solid-Vapor Diffusion Solid samples of Compound 2 were exposed to organic vapors in a sealed chamber. After a period of time, the Compound 2 solids were removed and characterized.
• Rotary Evaporation (Roto-vap): Filtered solutions containing Compound 2 were placed onto a Buchi Rotavapor R-l 14. The samples were kept at ambient temperature as the volumes were reduced under vacuum. Solids collected after all the solvent had been removed from the samples. An enabling form study was carried out at ambient, elevated (approximately 60 e C) and sub-ambient (2-8 °C) temperature (Table 8). All generated materials were Compound 2 Form 1.
• Figure 13 is the indexed XRPD pattern.
• Table 10 provides the data measurement of Compound 2 Form I.
• Table 11 provides the observed peaks of the XRPD and the prominent peaks are labeled with an asterisk.
• XRPD patterns were collected with a PANalytical XPert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source.
• An elliptically graded multilayer mirror was used to focus Cu Ka X-rays through the specimen and onto the detector.
• a silicon specimen NIST SRM 640e was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position.
• a specimen of the sample was sandwiched between 3-pm-thick films and analyzed in transmission geometry.
• a beam-stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air.
• Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. The data acquisition parameters for each pattern are displayed above the image in the Data section of this report.
• X'Celerator scanning position-sensitive detector
• thermogram DSC (Differential Scanning Calorimetry) was performed using a TA Instruments Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed into an aluminum DSC pan, covered with a lid, and the weight was accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The data acquisition parameters and pan configuration for each thermogram are displayed in the image in the Data section of this report. The method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate; e.g., -30-250-10 means "from -30 °C to 250 °C, at 10 °C/min". The following table summarizes the abbreviations used in each image for pan configurations:
• Modulated Differential Scanning Calorimetry (mDSC) data were obtained on a TA Instruments Q2000 differential scanning calorimeter equipped with a refrigerated cooling system (RCS). Temperature calibration was performed using NIST-traceable indium metal. The sample was placed into an aluminum DSC pan, and the weight was accurately recorded. The pan was covered with a lid perforated with a laser pinhole, and the lid was crimped. A weighed, crimped aluminum pan was placed on the reference side of the cell. Data were obtained using a modulation amplitude of ⁇ 0.8 °C and a 60 second period with an underlying heating rate of 2 °C/minute from 30 to 250 °C. The reported glass transition temperatures are obtained from the inflection point of the step change in the reversing heat flow versus temperature curve.
• Thermogravimetric (TG) TG analyses were performed using a TA Instruments Q5000 IR thermogravimetric analyzer. Temperature calibration was performed using nickel and AlumelTM. Each sample was placed in an aluminum pan. The sample was hermetically sealed, the lid pierced, then inserted into the TG furnace. The furnace was heated under nitrogen. The data acquisition parameters for each thermogram are displayed in the image in the Data section of this report.
• the method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate; e.g., 25-350-10 means "from 25 °C to 350 °C, at 10 °C/min".
• Hot stage microscopy was performed using a Linkam hot stage (FTIR 600) mounted on a Leica DM LP microscope equipped with a SPOT InsightTM color digital camera. Temperature calibrations were performed using USP melting point standards. Samples were placed on a cover glass, and a second cover glass was placed on top of the sample. As the stage was heated, each sample was visually observed using crossed polarizers and a first order red compensator. Images were captured using SPOT software (v. 4.5.9).

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