[go: up one dir, main page]

WO2024218503A1 - Formes solides d'un inhibiteur d'enzyme et sels associés - Google Patents

Formes solides d'un inhibiteur d'enzyme et sels associés Download PDF

Info

Publication number
WO2024218503A1
WO2024218503A1 PCT/GB2024/051019 GB2024051019W WO2024218503A1 WO 2024218503 A1 WO2024218503 A1 WO 2024218503A1 GB 2024051019 W GB2024051019 W GB 2024051019W WO 2024218503 A1 WO2024218503 A1 WO 2024218503A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
dsc
salt
crystalline form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/GB2024/051019
Other languages
English (en)
Inventor
Alexander Richard Liam Cecil
Stephen Gorsuch
Gillian Moore
Julian Scott Northen
Calum James SPOONER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kalvista Pharmaceuticals Ltd
Original Assignee
Kalvista Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kalvista Pharmaceuticals Ltd filed Critical Kalvista Pharmaceuticals Ltd
Publication of WO2024218503A1 publication Critical patent/WO2024218503A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to new solid forms of an enzyme inhibitor that is an inhibitor of Factor XIIa (FXIIa), a pharmaceutical composition containing them and their use in therapy. Also provided are processes for preparing the solid forms of the present invention.
  • Inhibitors of factor XIIa (FXIIa) have a number of possible therapeutic applications, particularly in the treatment of diseases or conditions in which factor XIIa inhibition is implicated.
  • FXIIa is a serine protease (EC 3.4.21.38) derived from its zymogen precursor, Factor XII (FXII), which is expressed by the F12 gene.
  • Single chain FXII has a low level of amidolytic activity that is increased upon interaction with negatively charged surfaces and has been implicated in its activation (see Invanov et al., Blood. 2017 Mar 16;129(11):1527-1537. doi: 10.1182/blood-2016-10-744110).
  • Proteolytic cleavage of FXII to heavy and light chains of FXIIa dramatically increases catalytic activity.
  • FXIIa that retains its full heavy chain is ⁇ FXIIa.
  • FXIIa that retains a small fragment of its heavy chain is ⁇ FXIIa.
  • the separate catalytic activities of ⁇ FXIIa and ⁇ FXIIa contribute to the activation and biochemical functions of FXIIa.
  • FXIIa has a unique and specific structure that is different from many other serine proteases. For instance, the Tyr99 in FXIIa points towards the active site, partially blocking the S2 pocket and giving it a closed characteristic. Other serine proteases containing a Tyr99 residue (e.g. FXa, tPA and FIXa) have a more open S2 pocket. Moreover, in several trypsin-like serine proteases the P4 pocket is lined by an “aromatic box” which is responsible for the P4-driven activity and selectivity of the corresponding inhibitors.
  • FXIIa has an incomplete “aromatic box” resulting in more open P4 pocket. See e.g. “Crystal structures of the recombinant ⁇ -factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics” M. Pathak et al., Acta. Cryst.2019, D75, 1-14; “Structures of human plasma ⁇ –factor XIIa cocrystallized with potent inhibitors” A Dementiev et al., Blood Advances 2018, 2(5), 549-558; “Design of Small-Molecule Active-Site Inhibitors of the S1A Family Proteases as Procoagulant and Anticoagulant Drugs” P. M.
  • FXIIa converts plasma prekallikrein (PK) to plasma kallikrein (PKa), which provides positive feedback activation of FXII to FXIIa.
  • PK plasma prekallikrein
  • PKa plasma kallikrein
  • HK high molecular weight kininogen
  • FXIIa mediated conversion of plasma prekallikrein to plasma kallikrein can cause subsequent cleavage of HK to generate bradykinin, a potent inflammatory hormone that can also increase vascular permeability, which has been implicated in disorders such as hereditary angioedema (HAE).
  • HAE hereditary angioedema
  • the contact system is activated via a number of mechanisms, including interactions with negatively charged surfaces, negatively charged molecules, unfolded proteins, artificial surfaces, foreign tissue (e.g. biological transplants, that include bio-prosthetic heart valves, and organ/tissue transplants), bacteria, and biological surfaces (including endothelium and extracellular matrix) that mediate assembly of contact system components.
  • the contact system is activated by plasmin, and cleavage of FXII by other enzymes can facilitate its activation.
  • Activation of the contact system leads to activation of the kallikrein kinin system (KKS), complement system, and intrinsic coagulation pathway (see https://www.genome.jp/kegg- bin/show_pathway?map04610).
  • FXIIa has additional substrates both directly, and indirectly via PKa, including Proteinase-activated receptors (PARs), plasminogen, and neuropeptide Y (NPY) which can contribute to the biological activity of FXIIa.
  • PARs Proteinase-activated receptors
  • NPY neuropeptide Y
  • PKa activation of PAR2 mediates neuroinflammation and may contribute to neuroinflammatory disorders including multiple sclerosis (see Göbel et al., Proc Natl Acad Sci U S A.2019 Jan 2;116(1):271- 276. doi: 10.1073/pnas.1810020116).
  • PKa activation of PAR1 and PAR2 on vascular smooth muscle cells has been implicated in vascular hypertrophy and atherosclerosis (see Abdallah et al., J Biol Chem. 2010 Nov 5;285(45):35206-15. doi: 10.1074/jbc.M110.171769).
  • FXIIa activation of plasminogen to plasmin contributes to fibrinolysis (see Konings et al., Thromb Res. 2015 Aug;136(2):474-80. doi: 10.1016/j.thromres.2015.06.028).
  • PKa proteolytically cleaves NPY and thereby alters its binding to NPY receptors (Abid et al., J Biol Chem. 2009 Sep 11;284(37):24715-24. doi: 10.1074/jbc.M109.035253).
  • Inhibition of FXIIa could provide clinical benefits by treating diseases and conditions caused by PAR signaling, NPY metabolism, and plasminogen activation.
  • BK bradykinin
  • Garadacimab (CSL- 312), a monoclonal antibody inhibitory against FXIIa, recently completed a phase 3 study where monthly prophylactic subcutaneous treatment was reported to reduce attacks in patients with type I/II hereditary angioedema (HAE), which results in intermittent swelling of face, hands, throat, gastro-intestinal tract and genitals (see https://www.clinicaltrials.gov/ct2/show/NCT04656418 and Craig et al., The Lancet. 2023;401(10382):1079-1090. doi: 10.1016/S0140-6736(23)00350-1).
  • HAE hereditary angioedema
  • FXIIa mediates the generation of PK to PKa
  • inhibitors of FXIIa could provide protective effects of all form of BK-mediated angioedema, including HAE and non-hereditary bradykinin-mediated angioedema (BK-AEnH).
  • BK-AEnH non-hereditary bradykinin-mediated angioedema
  • HAE type 1 HAE type 1
  • HAE type 2 normal C1 inhibitor HAE (normal C1-Inh HAE).
  • HAE type 1 is caused by mutations in the SERPING1 gene that lead to reduced levels of C1 inhibitor in the blood.
  • HAE type 2 is caused by mutations in the SERPING1 gene that lead to dysfunction of the C1 inhibitor in the blood.
  • the cause of normal C1-Inh HAE is less well defined and the underlying genetic dysfunction/fault/mutation can sometimes remain unknown.
  • Normal C1-Inh HAE can be diagnosed by reviewing the family history and noting that angioedema has been inherited from a previous generation (and thus it is hereditary angioedema). Normal C1-Inh HAE can also be diagnosed by determining that there is a dysfunction/fault/mutation in a gene other than those related to C1 inhibitor. For example, it has been reported that dysfunction/fault/mutation with plasminogen can cause normal C1-Inh HAE (see e.g. Veronez et al., Front Med (Lausanne).2019 Feb 21;6:28.
  • BK-AEnH bradykinin mediated angioedema non-hereditary
  • HAE bradykinin mediated angioedema non-hereditary
  • BK-AEnH is characterised by recurrent acute attacks where fluids accumulate outside of the blood vessels, blocking the normal flow of blood or lymphatic fluid and causing rapid swelling of tissues such as in the hands, feet, limbs, face, intestinal tract, airway or genitals.
  • BK-AEnH include: non hereditary angioedema with normal C1 Inhibitor (AE-nC1 Inh), which can be environmental, hormonal, or drug induced; acquired angioedema; anaphylaxis associated angioedema; angiotensin converting enzyme (ACE) inhibitor induced angioedema; dipeptidyl peptidase 4 inhibitor induced angioedema; and tPA induced angioedema (tissue plasminogen activator induced angioedema).
  • AE-nC1 Inh non hereditary angioedema with normal C1 Inhibitor
  • ACE angiotensin converting enzyme
  • dipeptidyl peptidase 4 inhibitor induced angioedema
  • tPA induced angioedema tissue plasminogen activator induced angioedema
  • AE-nC1 Inh Environmental factors that can induce AE-nC1 Inh include air pollution (Kedarisetty et al, Otolaryngol Head Neck Surg. 2019 Apr 30:194599819846446. doi: 10.1177/0194599819846446) and silver nanoparticles such as those used as antibacterial components in healthcare, biomedical and consumer products (Long et al., Nanotoxicology.2016;10(4):501-11. doi: 10.3109/17435390.2015.1088589).
  • Various publications suggest a link between the bradykinin and contact system pathways and BK-AEnHs, and also the potential efficacy of treatments, see e.g.: Bas et al.
  • BK-medicated AE can be caused by thrombolytic therapy.
  • tPA induced angioedema is discussed in various publications as being a potentially life threatening complication following thrombolytic therapy in acute stroke victims (see e.g. Sim ⁇ o et al., Blood. 2017 Apr 20;129(16):2280-2290. doi: 10.1182/blood-2016-09-740670; Fröhlich et al., Stroke. 2019 Jun 11:STROKEAHA119025260.
  • bradykinin mediated angioedema can be precipitated by estrogen contraception, so called “oestrogen associated angioedema”.
  • contact system mediated activation of the KKS has also been implicated in retinal edema and diabetic retinopathy (see Liu et al., Biol Chem. 2013 Mar;394(3):319-28. doi: 10.1515/hsz-2012-0316).
  • FXIIa concentrations are increased in the vitreous fluid from patients with advance diabetic retinopathy and in Diabetic Macular Edema (DME) (see Gao et al., Nat Med.2007 Feb;13(2):181-8. Epub 2007 Jan 28 and Gao et al., J Proteome Res. 2008 Jun;7(6):2516-25. doi: 10.1021/pr800112g).
  • FXIIa has been implicated in mediating both vascular endothelial growth factor (VEGF) independent DME (see Kita et al., Diabetes. 2015 Oct;64(10):3588-99.
  • VEGF vascular endothelial growth factor
  • FXII deficiency is protective against VEGF induced retinal edema in mice (Clermont et al., ARVO talk 2019). Therefore it has been proposed that FXIIa inhibition will provide therapeutic effects for diabetic retinopathy and retinal edema caused by retinal vascular hyperpermeability, including DME, retinal vein occlusion, age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • FXIIa has been implicated in the treatment of sepsis and bacterial sepsis (see Morrison et al., J Exp Med. 1974 Sep 1;140(3):797-811). Therefore, FXIIa inhibitors could provide therapeutic benefits in treating sepsis, bacterial sepsis and disseminated intravascular coagulation (DIC).
  • FXIIa mediated activation of the KKS and production of BK have been implicated in neurodegenerative diseases including Alzheimer's disease, multiple sclerosis, epilepsy and migraine (see Zamolodchikov et al., Proc Natl Acad Sci U S A.2015 Mar 31;112(13):4068-73.
  • FXIIa inhibitors could provide therapeutic benefits in reducing the progression and clinical symptoms of these neurodegenerative diseases.
  • FXIIa has also been implicated in anaphylaxis (see Bender et al., Front Immunol.2017 Sep 15;8:1115.
  • FXIIa inhibitors could provide therapeutic benefits in reducing the clinical severity and incidence of anaphylactic reactions.
  • the role of FXIIa in coagulation was identified over 50 years ago, and has been extensively documented in publications using biochemical, pharmacological, genetic and molecular studies (see Davie et al., Science. 1964 Sep 18;145(3638):1310-2).
  • FXIIa mediated activation of factor XI (FXI) triggers the intrinsic coagulation pathway.
  • FXIIa can increase coagulation in a FXI independent manner (see Radcliffe et al., Blood. 1977 Oct;50(4):611-7; and Puy et al., J Thromb Haemost.2013 Jul;11(7):1341-52. doi: 10.1111/jth.12295).
  • FXII deficiency prolongs activated partial prothrombin time (APTT) without adversely affecting hemostasis (see Renné et al., J Exp Med.2005 Jul 18;202(2):271- 81; and Sim ⁇ o et al., Front Med (Lausanne). 2017 Jul 31;4:121.
  • FXIIa inhibitors could be used to treat a spectrum of prothrombotic conditions including venous thromboembolism (VTE); cancer associated thrombosis; complications caused by mechanical and bioprosthetic heart valves, catheters, extracorporeal membrane oxygenation (ECMO), left ventricular assisted devices (LVAD), dialysis, cardiopulmonary bypass (CPB); sickle cell disease, joint arthroplasty, thrombosis induced by tPA, Paget-Schroetter syndrome and Budd-Chari syndrome.
  • FXIIa inhibitor could be used for the treatment and/or prevention of thrombosis, edema, and inflammation associated with these conditions. Surfaces of medical devices that come into contact with blood can cause thrombosis.
  • FXIIa inhibitors may also be useful for treating or preventing thromboembolism by lowering the propensity of devices that come into contact with blood to clot blood.
  • devices that come into contact with blood include vascular grafts, stents, in-dwelling catheters, external catheters, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems.
  • Preclinical studies have shown that FXIIa has been shown to contribute to stroke and its complications following both ischemic stroke, and hemorrhagic accidents (see Barbieri et al., J Pharmacol Exp Ther. 2017 Mar;360(3):466-475. doi: 10.1124/jpet.116.238493; Krupka et al., PLoS One.
  • FXIIa inhibition may improve clinical neurological outcomes in the treatment of patients with stroke.
  • FXII deficiency has been shown to reduce the formation of atherosclerotic lesions in Apoe ⁇ / ⁇ mice (Didiasova et al., Cell Signal. 2018 Nov;51:257-265. doi: 10.1016/j.cellsig.2018.08.006). Therefore, FXIIa inhibitors could be used in the treatment of atherosclerosis.
  • FXIIa either directly, or indirectly via PKa, has been shown to activate the complement system (Ghebrehiwet et al., Immunol Rev.2016 Nov;274(1):281-289. doi: 10.1111/imr.12469).
  • BK increases complement C3 in the retina, and an in vitreous increase in complement C3 is associated with DME (Murugesan et al., Exp Eye Res.2019 Jul 24;186:107744. doi: 10.1016/j.exer.2019.107744). Both FXIIa and PKa activate the complement system (see Irmscher et al., J Innate Immun.2018;10(2):94-105. doi: 10.1159/000484257; and Ghebrehiwet et al., J Exp Med.1981 Mar 1;153(3):665-76).
  • idiopathic Pulmonary Fibrosis through direct stimulation of fibroblasts to produce pro-fibrotic cytokine IL-6.
  • McKenzie et al. (“A phase I, first-in-human, randomized dose-escalation study of anti-activated factor XII monoclonal antibody garadacimab”, Clin Transl Sci. 2022;15:626-637. doi:10.1111/cts.13180) reports on a phase 1 study of garadacimab (CSL312), a FXIIa inhibitor, and indicates that garadacimab has the potential to block bradykinin production and thus prevent attacks of edema in HAE.
  • an undesirable off-target effect is bleeding.
  • Off- target effects can be made even worse (i.e. there is typically a higher likelihood of poor selectivity and off-target effects) if the inhibitor is a covalent binder. Therefore, there remains a need to develop new FXIIa inhibitors that are highly selective for FXIIa in order to e.g. mitigate the risks of non-selectivity and cytotoxicity. There also remains a need to develop new FXIIa inhibitors that are not covalent inhibitors to mitigate the risks of non-selectivity and cytotoxicity. There is a particular need to develop small molecule FXIIa inhibitors, particularly as an oral therapy.
  • the compound of Formula A has been carefully developed to be an inhibitor of FXIIa, which as noted above, has a unique and specific binding site. Furthermore, the compound of Formula A has been carefully developed to (i) show selectivity for FXIIa over other serine proteases, thus reducing the risk of off-target effects and cytotoxicity, and (ii) to possess characteristics that can be considered suitable for oral delivery e.g. a suitable oral availability profile.
  • the compound of Formula A does not contain groups associated with covalent binding properties e.g. groups with acylating reactivity such as acylated aminotriazoles, and thus acts as a reversible inhibitor, to further reduce the risk of off-target effects and cytotoxicity.
  • the present invention provides crystalline solid forms of a free base of the compound of Formula A. Preferably, this form is referred to as Form 1.
  • the present invention also provides crystalline solid forms of salts of the compound of Formula A.
  • the invention provides crystalline solid forms of a mesylate salt of the compound of Formula A. Preferably, this form is referred to as Form 10.
  • the crystalline mesylate salt of the compound of Formula A (Form 10) and the crystalline free base of the compound of Formula A (Form 1) demonstrate form stability to temperature and humidity, as shown in the examples. These crystalline forms can demonstrate properties indicating good pharmaceutical utility.
  • the present invention also provides novel solid forms of salts of the compound of Formula A, specifically maleate, hydrochloride, tosylate, mesylate, malate, hemi-malate, tartrate, succinate, hemi-succinate, phosphate, hydrobromide, malonate, hemi-malonate, fumarate, hemi-fumarate, gentisate, citrate, sulphate, besylate, naphthalene-1,5-disulfonate, and benzoate salts of the compound of Formula A.
  • the compound of Formula A is (R)-N5-((4-methyl-6-(6-methyl-3-(trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-3-yl)methyl)isoquinoline-1,5-diamine, as shown below.
  • This is Example 1342 in WO2022/118016: Formula A
  • solid form as used herein includes crystalline forms and amorphous forms.
  • the solid forms of the invention are crystalline forms.
  • the term “mesylate salt” as used herein means the acid addition salt formed between methane sulfonic acid and the compound of Formula A.
  • solid forms of the invention can be provided as one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and trans-forms, E- and Z- forms, R-, S- and meso-forms, keto-, and enol-forms, unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof.
  • such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques).
  • such isomers can be prepared by the application or adaptation of known methods (e.g. asymmetric synthesis).
  • X-ray powder diffraction peaks are measured using Cu K ⁇ radiation.
  • the term “approximately” means that there is an uncertainty in the measurements of the degrees 2 ⁇ of ⁇ 0.5 (expressed in degrees 2 ⁇ ), preferably ⁇ 0.3 (expressed in degrees 2 ⁇ ), more preferably ⁇ 0.2 (expressed in degrees 2 ⁇ ) or even more preferably ⁇ 0.1 (expressed in degrees 2 ⁇ ).
  • the term “approximately” can mean that there is an uncertainty in the measurements of the degrees 2 ⁇ of ⁇ 0.5 (expressed in degrees 2 ⁇ ).
  • the term “approximately” can mean that there is an uncertainty in the measurements of the degrees 2 ⁇ of ⁇ 0.3 (expressed in degrees 2 ⁇ ).
  • the term “approximately” can mean that there is an uncertainty in the measurements of the degrees 2 ⁇ of ⁇ 0.2 (expressed in degrees 2 ⁇ ).
  • the term “approximately” can mean that there is an uncertainty in the measurements of the degrees 2 ⁇ of ⁇ 0.1 (expressed in degrees 2 ⁇ ).
  • the term “about” means ⁇ 20%.
  • the term “about” can also mean ⁇ 10%.
  • the term “about” can also mean ⁇ 5%. For instance, “about 50%” means “40% to 60%” when “about” is ⁇ 20%.
  • the term “about” can mean ⁇ 20°C. Alternatively, when used in the context of temperature values, the term “about” can mean ⁇ 10°C. Alternatively, when used in the context of temperature values, the term “about” can mean ⁇ 5°C. Alternatively, when used in the context of temperature values, the term “about” can mean ⁇ 2°C. Alternatively, when used in the context of temperature values, the term “about” can mean ⁇ 1°C. For instance, “about 100°C” means “80-120°C”, when “about” is ⁇ 20°C.
  • the X-ray powder diffraction pattern of a solid form may be described herein as "substantially" the same as that depicted in a Figure.
  • the peaks in X-ray powder diffraction patterns may be slightly shifted in their positions and relative intensities due to various factors known to the skilled person. For example, shifts in peak positions or the relative intensities of the peaks of a pattern can occur because of the equipment used, method of sample preparation, preferred packing and orientations, the radiation source, and method and length of data collection.
  • the skilled person will be able to compare the X-ray powder diffraction patterns shown in the figures herein with those of an unknown solid form to confirm the identity of the solid form.
  • the skilled person is familiar with techniques for measuring XRPD patterns.
  • the X-ray powder diffraction pattern of the sample of compound may be recorded using a PANalytical diffractometer according to the experimental conditions explained in the General Experimental section of this application.
  • X-Ray Power Diffraction (XRPD) X-Ray Powder Diffraction patterns were collected on a PANalytical diffractometer using Cu K ⁇ radiation (45kV, 40mA), ⁇ - ⁇ goniometer, focusing mirror, divergence slit (1/2’’), soller slits at both incident and divergent beam (4mm) and a PIXcel detector.
  • the software used for data collection was X’Pert Data Collector, version 2.2f and the data was presented using X’Pert Data Viewer, version 1.2d.
  • Solid forms of the free base of the compound of Formula A The present invention provides solid forms of the free base of the compound of Formula A. More specifically, the present invention provides crystalline solid forms of the free base of the compound of Formula A. The invention provides a crystalline solid form of the free base of the compound of Formula A, which is herein referred to as ‘Form 1’.
  • the present invention provides a crystalline solid form (Form 1) of the free base compound of Formula A, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu K ⁇ radiation, expressed in degrees 2 ⁇ ) at approximately: (1) 7.7, 10.4, 15.5, 19.9, and 21.0; or (2) 5.4, 7.7, 10.4, 15.5, 19.5, 19.9, and 21.0; or (3) 5.4, 7.7, 10.4, 12.4, 13.3, 15.5, 19.5, 19.9, 21.0, and 23.5.
  • Form 1 characteristic X-ray powder diffraction peaks
  • the present invention also provides a crystalline solid form (Form 1) of the free base of the compound of Formula A, having an X ray powder diffraction pattern comprising characteristic peaks (expressed in degrees 2 ⁇ ) at approximately 5.4, 7.7, 8.6, 10.4, 12.4, 13.3, 15.5, 18.8, 19.5, 19.9, and 21.0.
  • the present invention also provides a crystalline solid form (Form 1) of the free base of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 2a.
  • the present invention provides a crystalline solid form (Form 1) of the free base of the compound of Formula A, which exhibits an endothermic peak in its DSC thermograph at 216 ⁇ 3 °C, preferably 216 ⁇ 2 °C, more preferably 216 ⁇ 1 °C.
  • the present invention provides a crystalline solid form (Form 1) of the free base of the compound of Formula A, having a DSC/TGA overlay thermograph substantially the same as that shown in Figure 2b.
  • the DSC/TGA thermograph of the sample of compound may be recorded according to the method outlined in the General Experimental section of this application.
  • the present invention provides a crystalline solid form (Form 1) of the free base of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention also provides a process for the preparation of a crystalline solid form (Form 1) of the free base of the compound of Formula A, said process comprising the crystallisation of said crystalline form from a solution of the compound of Formula A.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the compound of Formula A in a solvent or mixture of solvents.
  • the solvent is tert-butyl methyl ether, cyclopentyl methyl ether, EtOAc, isopropyl acetate, anisole, toluene, chlorobenzene, cumene, heptane, or cyclohexane.
  • the present invention also provides a process for the preparation of a crystalline solid form (Form 1) of the free base of the compound of Formula A, said process comprising crystallisation of the compound of Formula A by slow evaporation from various solvents.
  • the solvent is, 2-methyltetrahydrofuran, 1,4-dioxane, acetone, or methyl isobutyl ketone.
  • said process may comprise thermal cycling of the compound of Formula A.
  • the invention also provides a method of processing a crystalline solid form of the free base of the compound of Formula A (as described herein) into a medicament.
  • the invention provides a method of processing a crystalline solid form the free base of the compound of Formula A (as described herein) into a medicament.
  • the invention provides a method of processing a crystalline solid form (Form 1) of the free base of the compound of Formula A into a medicament.
  • Solid forms of the mesylate salt of the compound of Formula A The present invention provides a solid form of a mesylate salt of the compound of Formula A. More specifically, the invention provides a crystalline solid form of a mesylate salt of the compound of Formula A. More specifically, the invention provides a crystalline solid form of a mesylate salt of the compound of Formula A, which is herein referred to as ‘Form 10’.
  • the present invention provides a crystalline solid form (Form 10) of the mesylate salt of the compound of Formula A, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu K ⁇ radiation, expressed in degrees 2 ⁇ ) at approximately: (1) 13.914.7, 16.8, 17.6, and 20.3; or (2) 11.3, 11.7, 13.914.7, 16.8, 17.6, and 20.3; or (3) 10.5, 11.3, 11.7, 13.914.7, 15.8, 16.8, 17.6, 19.0 and 20.3.
  • Form 10 characteristic X-ray powder diffraction peaks
  • the present invention also provides a crystalline solid form (Form 10) of the mesylate salt of the compound of Formula A, having an X-ray powder diffraction pattern comprising characteristic peaks (expressed in degrees 2 ⁇ ) at approximately 4.6, 5.4, 9.4, 10.5, 11.3, 11.7, 12.7, 13.914.7, 15.8, 16.6, 16.8, 17.6, 18.2, 18.4, 19.0, 19.3, and 20.3.
  • the present invention also provides a crystalline solid form (Form 10) of the mesylate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 11a.
  • the present invention provides a crystalline solid form (Form 10) of the mesylate salt of the compound of Formula A, which exhibits an endothermic peak in its DSC thermograph at 223 ⁇ 3 °C, preferably 223 ⁇ 2 °C, more preferably 223 ⁇ 1 °C.
  • the present invention provides a crystalline solid form (Form 10) of the mesylate salt of the compound of Formula A, having a DSC/TGA overlay thermograph substantially the same as that shown in Figure 11b.
  • the present invention provides a crystalline solid form (Form 10) of the mesylate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention also provides a process for the preparation of the mesylate salts of the compound of Formula A (e.g. crystalline Form 10), as described herein.
  • the present invention provides a process for the preparation of crystalline solid Form 10 of the present invention, said process comprising the crystallisation of said crystalline solid form from a solution of the mesylate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the mesylate salt of the compound of Formula A can be formed by adding methanesulfonic acid to a solution or suspension of the compound of Formula A in a solvent or mixture of solvents.
  • the solvent can be THF, EtOH or MEK.
  • the solvent selected is THF.
  • the invention also provides a method of processing the mesylate salt of the compound of Formula A into a medicament. Specifically, the invention provides a method of processing crystalline solid Form 10 into a medicament.
  • Compositions comprising the crystalline forms of the invention The invention also provides compositions comprising crystalline solid forms of the compound of Formula A (as described herein), wherein the composition is substantially free of amorphous compound of Formula A.
  • These compositions can be comprised within, inter alia, the pharmaceutical compositions described herein.
  • the term “substantially free of amorphous compound of Formula A” means that the composition contains no significant amount of amorphous compound of Formula A. At least about 90% by weight of the composition can be a crystalline solid form of the compound of Formula A.
  • At least about 95% by weight of the composition can be a crystalline solid form of the compound of Formula A. More specifically, at least about 97%, 98% or 99% by weight of the composition can be a crystalline solid form of the compound of Formula A.
  • the composition can contain less than about 50% by weight of amorphous compound of Formula A.
  • the composition can contain less than about 30% by weight of amorphous compound of Formula A.
  • the composition can contain less than about 20% by weight of amorphous compound of Formula A.
  • the composition can contain less than about 10% by weight of amorphous compound of Formula A.
  • the composition can contain less than about 5% by weight of amorphous compound of Formula A.
  • the composition can contain less than about 3%, 2% or 1% by weight of amorphous compound of Formula A.
  • the invention also provides compositions comprising the crystalline solid form of the free base of the compound of Formula A (e.g. Form 1), wherein the composition is substantially free of amorphous compound of Formula A.
  • the invention also provides compositions comprising the crystalline solid form of the mesylate salt of the compound of Formula A (e.g. Form 10), wherein the composition is substantially free of amorphous compound of Formula A.
  • Other solid forms provided by the invention The invention also provides a crystalline solid form of the free base of the compound of Formula A, which is herein referred to as ‘Form 2’.
  • the present invention also provides a crystalline solid form (Form 2) of the free base of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 3a.
  • the present invention provides a crystalline solid form (Form 2) of the free base of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 3b.
  • the present invention provides a crystalline solid form (Form 2) of the free base of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention provides both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of Formula A and an amount of one or more solvents.
  • the term 'hydrate' is employed when the solvent is water.
  • the present invention provides a solvate of the solid form (Form 2) of the free base of the compound of Formula A.
  • the present invention also provides a solid form of the hydrate of the of the free base of the compound of Formula A.
  • the present invention also provides a process for the preparation of a crystalline solid form (Form 2) of the free base compound of Formula A, as described herein.
  • the present invention provides a process for the preparation of a crystalline solid form (Form 2) of the free base compound of Formula A, said process comprising the crystallisation of said solid form from a solution of the compound of Formula A.
  • the present invention provides a process for the preparation of a crystalline solid form (Form 2) of the free base compound of Formula A, said process comprising crystallisation of the compound of Formula A by slow evaporation from various solvents.
  • the solvent is MeOH, THF or DCM.
  • the applicant has also developed other novel solid forms of salts of the compound of Formula A, specifically maleate, hydrochloride, tosylate, mesylate, malate, hemi-malate, tartrate, succinate, hemi-succinate, phosphate, hydrobromide, malonate, hemi-malonate, fumarate, hemi-fumarate, and gentisate salts of the compound of Formula A.
  • the present invention provides a specific solid form of the maleate salt of the compound of Formula A. Specifically, this can be referred to as ‘Form 3’.
  • maleate as used herein when referring to a salt of the compound of Formula A is intended to encompass both a mono-maleate salt and a hemi-maleate salt.
  • the maleate salt can be a mono- maleate salt.
  • the maleate salt can be a hemi-maleate salt.
  • the present invention also provides a solid form (Form 3) of the maleate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 4a.
  • the present invention provides a crystalline solid form (Form 3) of the of the maleate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 4b.
  • the present invention provides a crystalline solid form (Form 3) of the maleate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention provides specific solid forms of the hydrochloride salt of the compound of Formula A. Specifically, these can be referred to as ‘Form 4’ and ‘Form 5’.
  • the present invention also provides a solid form (Form 4) of the hydrochloride salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 5a.
  • the present invention provides a crystalline solid form (Form 4) of the hydrochloride salt of the compound of Formula A, having a DSC thermograph substantially the same as that shown in Figure 5b.
  • the present invention provides a crystalline solid form (Form 4) of the hydrochloride salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC thermograph as described above.
  • the present invention also provides a solid form (Form 5) of the hydrochloride salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 6a.
  • the present invention provides a crystalline solid form (Form 5) of the hydrochloride salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 6b.
  • the present invention provides a crystalline solid form (Form 5) of the hydrochloride salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention provides specific solid forms of the tosylate salt of the compound of Formula A. Specifically, these can be referred to as ‘Form 6’, ‘Form 7’, Form 8’, and ‘Form 9’.
  • the present invention also provides a solid form (Form 6) of the tosylate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 7a.
  • the present invention provides a crystalline solid form (Form 6) of the tosylate salt of the compound of Formula A, having a DSC thermograph substantially the same as that shown in Figure 7b.
  • the present invention provides a crystalline solid form (Form 6) of the tosylate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC thermograph as described above.
  • the present invention also provides a solid form (Form 7) of the tosylate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 8a.
  • the present invention provides a crystalline solid form (Form 7) of the tosylate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 8b.
  • the present invention provides a crystalline solid form (Form 7) of the tosylate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention also provides a solid form (Form 8) of the tosylate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 9a.
  • the present invention provides a crystalline solid form (Form 8) of the tosylate salt of the compound of Formula A, having a DSC thermograph substantially the same as that shown in Figure 9b and a TGA thermograph substantially the same as that shown in Figure 9c.
  • the present invention provides a crystalline solid form (Form 8) of the tosylate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, a DSC thermograph as described above and a TGA thermograph as described above.
  • the present invention also provides a solid form (Form 9) of the tosylate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 10a.
  • the present invention provides a crystalline solid form (Form 9) of the tosylate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 10b.
  • the present invention provides a crystalline solid form (Form 9) of the tosylate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention provides specific solid forms of the malate salt of the compound of Formula A.
  • the term “malate” as used herein when referring to a salt of the compound of Formula A is intended to encompass both a mono-malate salt and a hemi-malate salt.
  • the malate salt can be a mono-malate salt.
  • the malate salt can be a hemi-malate salt.
  • the present invention also provides a solid form (Form 11) of the malate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 12a.
  • the present invention provides a crystalline solid form (Form 11) of the malate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 12b.
  • the present invention provides a crystalline solid form (Form 11) of the malate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention also provides a solid form (Form 12) of the malate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 13a.
  • the present invention provides a crystalline solid form (Form 12) of the malate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 13b.
  • the present invention provides a crystalline solid form (Form 12) of the malate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention provides a specific solid form of the tartrate salt of the compound of Formula A. Specifically, this can be referred to as ‘Form 13’.
  • the term “tartrate” as used herein when referring to a salt of the compound of Formula A is intended to encompass both a mono-tartrate salt and a hemi-tartrate salt.
  • the tartrate salt can be a mono-tartrate salt.
  • the tartrate salt can be a hemi-tartrate salt.
  • the present invention also provides a solid form (Form 13) of the tartrate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 14a.
  • the present invention provides a crystalline solid form (Form 13) of the tartrate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 14b.
  • the present invention provides a crystalline solid form (Form 13) of the tartrate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention provides specific solid forms of the succinate salt of the compound of Formula A. Specifically, these can be referred to as ‘Form 14’, ‘Form 15’ and ‘Form 16’.
  • the term “succinate” as used herein when referring to a salt of the compound of Formula A is intended to encompass both a mono-succinate salt and a hemi-succinate salt.
  • the succinate salt can be a mono-succinate salt.
  • the succinate salt can be a hemi-succinate salt.
  • the present invention also provides a solid form (Form 14) of the succinate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 15a.
  • the present invention provides a crystalline solid form (Form 14) of the succinate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 15b.
  • the present invention provides a crystalline solid form (Form 14) of the succinate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention also provides a solid form (Form 15) of the succinate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 16a.
  • the present invention provides a crystalline solid form (Form 15) of the succinate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 16b.
  • the present invention provides a crystalline solid form (Form 15) of the succinate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention also provides a solid form (Form 16) of the succinate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 17a.
  • the present invention provides a crystalline solid form (Form 16) of the succinate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 17b.
  • the present invention provides a crystalline solid form (Form 16) of the succinate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention provides a specific solid form of the phosphate salt of the compound of Formula A. Specifically, this can be referred to as ‘Form 17’.
  • the term “phosphate” as used herein when referring to a salt of the compound of Formula A is intended to encompass both a mono-phosphate salt and a hemi-phosphate salt.
  • the phosphate salt can be a mono-phosphate salt.
  • the phosphate salt can be a hemi-phosphate salt.
  • the phosphate salt can also be a trito-phosphate salt, which is a phosphate salt with a 3 base : 1 phosphate ratio.
  • the present invention also provides a solid form (Form 17) of the phosphate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 18a.
  • the present invention provides a crystalline solid form (Form 17) of the phosphate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 18b.
  • the present invention provides a crystalline solid form (Form 17) of the phosphate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention provides a specific solid form of the hydrobromic acid salt of the compound of Formula A. Specifically, this can be referred to as ‘Form 18’.
  • the present invention also provides a solid form (Form 18) of the hydrobromic acid salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 19a.
  • the present invention provides a crystalline solid form (Form 18) of the hydrobromic acid salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 19b.
  • the present invention provides a crystalline solid form (Form 18) of the hydrobromic acid salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention provides specific solid forms of the malonate salt of the compound of Formula A. Specifically, these can be referred to as ‘Form 19’ and ‘Form 20’.
  • malonate as used herein when referring to a salt of the compound of Formula A is intended to encompass both a mono-malonate salt and a hemi-malonate salt.
  • the malonate salt can be a mono-malonate salt.
  • the malonate salt can be a hemi-malonate salt.
  • the present invention also provides a solid form (Form 19) of the malonate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 20a.
  • the present invention provides a crystalline solid form (Form 19) of the malonate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 20b.
  • the present invention provides a crystalline solid form (Form 19) of the malonate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention also provides a solid form (Form 20) of the malonate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 21a.
  • the present invention provides a crystalline solid form (Form 20) of the malonate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 21b.
  • the present invention provides a crystalline solid form (Form 20) of the malonate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention provides specific solid forms of the fumarate salt of the compound of Formula A. Specifically, these can be referred to as ‘Form 21’, ‘Form 22’, ‘Form 23’, ‘Form 24’, ‘Form 25’, and ‘Form 26’.
  • the term “fumarate” as used herein when referring to a salt of the compound of Formula A is intended to encompass both a mono-fumarate salt and a hemi-fumarate salt.
  • the fumarate salt can be a mono- fumarate salt.
  • the fumarate salt can be a hemi-fumarate salt.
  • the present invention also provides a solid form (Form 21) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 22a.
  • the present invention provides a crystalline solid form (Form 21) of the fumarate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 22b.
  • the present invention provides a crystalline solid form (Form 21) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention also provides a solid form (Form 22) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 23a.
  • the present invention provides a crystalline solid form (Form 22) of the fumarate salt of the compound of Formula A, having a DSC thermograph substantially the same as that shown in Figure 23b.
  • the present invention provides a crystalline solid form (Form 22) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC thermograph as described above.
  • the present invention also provides a solid form (Form 23) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 24a.
  • the present invention provides a crystalline solid form (Form 23) of the fumarate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 24b.
  • the present invention provides a crystalline solid form (Form 23) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention also provides a solid form (Form 24) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 25a.
  • the present invention provides a crystalline solid form (Form 24) of the fumarate salt of the compound of Formula A, having a DSC thermograph substantially the same as that shown in Figure 25b.
  • the present invention provides a crystalline solid form (Form 24) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC thermograph as described above.
  • the present invention also provides a solid form (Form 25) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 26a.
  • the present invention provides a crystalline solid form (Form 25) of the fumarate salt of the compound of Formula A, having a DSC thermograph substantially the same as that shown in Figure 26b.
  • the present invention provides a crystalline solid form (Form 25) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC thermograph as described above.
  • the present invention also provides a solid form (Form 26) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 27a.
  • the present invention provides a crystalline solid form (Form 26) of the fumarate salt of the compound of Formula A, having a DSC thermograph substantially the same as that shown in Figure 27b.
  • the present invention provides a crystalline solid form (Form 26) of the fumarate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC thermograph as described above.
  • the present invention provides specific solid forms of the gentisate salt of the compound of Formula A. Specifically, these can be referred to as ‘Form 27’ and ‘Form 28’.
  • the present invention also provides a solid form (Form 27) of the gentisate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 28a.
  • the present invention provides a crystalline solid form (Form 27) of the gentisate salt of the compound of Formula A, having a DSC/TGA thermograph substantially the same as that shown in Figure 28b.
  • the present invention provides a crystalline solid form (Form 27) of the gentisate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC/TGA thermograph as described above.
  • the present invention also provides a solid form (Form 28) of the gentisate salt of the compound of Formula A having an X-ray powder diffraction pattern substantially the same as that shown in Figure 29a.
  • the present invention provides a crystalline solid form (Form 28) of the gentisate salt of the compound of Formula A, having a DSC thermograph substantially the same as that shown in Figure 29b.
  • the present invention provides a crystalline solid form (Form 28) of the gentisate salt of the compound of Formula A having an X-ray powder diffraction pattern as described above, and a DSC thermograph as described above.
  • a reference to a particular compound also includes all isotopic variants.
  • the solid forms of the present invention can exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and an amount of one or more pharmaceutically acceptable solvents, for example, EtOH.
  • the term 'hydrate' is used when the solvent is water.
  • the present invention encompasses solvates (e.g. hydrates) of the solid forms of the compound of Formula A and salts thereof described herein.
  • the present invention provides solvates of the solid forms of the salts of the compound of Formula A.
  • the present invention also provides hydrates of the solid forms of the salts of the compound of Formula A.
  • the present invention also provides compositions comprising the solid forms of the salts of the compound of Formula A, wherein the composition is substantially free of amorphous compound of Formula A.
  • the present invention also provides a process for the preparation of the maleate salt of the compound of Formula A, as described herein.
  • the present invention provides a process for the preparation of a crystalline solid form of the maleate salt of the compound of Formula A of the present invention (e.g. Form 3), said process comprising the crystallisation of said solid form from a solution of the maleate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the maleate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the maleate salt of the compound of Formula A can be formed by adding maleic acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent is MeOH, EtOH, or THF, e.g. when the solid form is Form 3.
  • an antisolvent may be added.
  • the solvent can be EtOH and the antisolvent can be EtOAc, or the solvent can be THF and the antisolvent can be DCM, e.g. when the solid form is Form 3.
  • the present invention also provides a process for the preparation of the hydrochloride salt of the compound of Formula A, as described herein.
  • the present invention provides a process for the preparation of a crystalline solid form of the hydrochloride salt of the compound of Formula A of the present invention (e.g. Forms 4, or 5), said process comprising the crystallisation of said solid form from a solution of the hydrochloride salt of the compound of Formula A in a solvent or a mixture of solvents.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the hydrochloride salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the hydrochloride salt of the compound of Formula A can be formed by adding hydrochloric acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent can be MeOH or THF.
  • the solvent can be MeOH, e.g. when the solid form is Form 4.
  • the solvent can be THF, e.g. when the solid form is Form 5.
  • an antisolvent may be added.
  • the solvent can be THF and the antisolvent can be DCM, e.g. when the solid form is Form 5.
  • the present invention also provides a process for the preparation of the tosylate salt of the compound of Formula A, as described herein. Specifically, the present invention provides a process for the preparation of a crystalline solid form of the tosylate salt of the compound of Formula A of the present invention (e.g.
  • said process comprising the crystallisation of said solid form from a solution of the tosylate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the tosylate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the tosylate salt of the compound of Formula A can be formed by adding p-toluene sulfonic acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent can be EtOH, MeOH, THF, MEK, or toluene.
  • the solvent can be MeOH or THF e.g. when the solid form is Form 6.
  • the solvent can be EtOH, e.g. when the solid form is Form 7.
  • the solvent can be MEK, e.g. when the solid form is Form 8.
  • the solvent can be toluene, e.g. when the solid form is Form 9.
  • Said process may also comprise trituration with an appropriate solvent.
  • the solvent can be toluene and heptane (e.g. when the solid form is Form 6) Alternatively, said process may comprise thermal cycling of a solid form of a tosylate salt of the compound of Formula A (e.g. when the solid form is Form 9).
  • the present invention also provides a process for the preparation of the malate salt of the compound of Formula A, as described herein.
  • the present invention provides a process for the preparation of a crystalline solid form of the malate salt of the compound of Formula A of the present invention (e.g. Forms 11 or 12), said process comprising the crystallisation of said solid form from a solution of the malate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the malate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the malate salt of the compound of Formula A can be formed by adding malic acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent can be EtOH or THF.
  • the solvent can be EtOH or THF e.g. when the solid form is Form 11.
  • the solvent can be EtOH, e.g. when the solid form is Form 12.
  • an antisolvent may be added.
  • the solvent can be EtOH and the antisolvent can be ethyl acetate, or the solvent can be THF and the antisolvent can be DCM e.g. when the solid form is Form 11.
  • the present invention also provides a process for the preparation of the tartrate salt of the compound of Formula A, as described herein. Specifically, the present invention provides a process for the preparation of a crystalline solid form of the tartrate salt of the compound of Formula A of the present invention (e.g.
  • Form 13 said process comprising the crystallisation of said solid form from a solution of the tartrate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the tartrate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the tartrate salt of the compound of Formula A can be formed by adding L-tartaric acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent can be EtOH.
  • the solvent can be EtOH e.g. when the solid form is Form 13.
  • an antisolvent may be added.
  • the solvent can be EtOH and the antisolvent can be heptane e.g. when the solid form is Form 13.
  • the present invention also provides a process for the preparation of the succinate salt of the compound of Formula A, as described herein. Specifically, the present invention provides a process for the preparation of a crystalline solid form of the succinate salt of the compound of Formula A of the present invention (e.g. Forms 14, 15, or 16), said process comprising the crystallisation of said solid form from a solution of the succinate salt of the compound of Formula A in a solvent or a mixture of solvents. Alternatively, said process may comprise the maturation or equilibration of said solid form from a suspension of the succinate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the succinate salt of the compound of Formula A can be formed by adding succinic acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent can be EtOH, THF, MEK, or MeOH.
  • the solvent can be EtOH or THF e.g. when the solid form is Form 14.
  • the solvent can be MEK, e.g. when the solid form is Form 15.
  • the solvent can be MeOH, e.g. when the solid form is Form 16.
  • an antisolvent may be added.
  • the solvent can be EtOH and the antisolvent can be ethyl acetate, or the solvent can be THF and the antisolvent can be DCM, e.g. when the solid form is Form 14.
  • the solvent can be MEK and the antisolvent can be IPA, e.g. when the solid form is Form 15. Said process may also comprise trituration with an appropriate solvent.
  • the solvent can be diethyl ether (e.g. when the solid form is Form 16)
  • the present invention also provides a process for the preparation of the phosphate salt of the compound of Formula A, as described herein. Specifically, the present invention provides a process for the preparation of a crystalline solid form of the phosphate salt of the compound of Formula A of the present invention (e.g. Form 17), said process comprising the crystallisation of said solid form from a solution of the phosphate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the phosphate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the phosphate salt of the compound of Formula A can be formed by adding phosphoric acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent can be EtOH.
  • the solvent can be EtOH e.g. when the solid form is Form 17.
  • an antisolvent may be added.
  • the solvent can be EtOH and the antisolvent can be ethyl acetate e.g. when the solid form is Form 17.
  • the present invention also provides a process for the preparation of the hydrobromide salt of the compound of Formula A, as described herein.
  • the present invention provides a process for the preparation of a crystalline solid form of the hydrobromide salt of the compound of Formula A of the present invention (e.g. Form 18), said process comprising the crystallisation of said solid form from a solution of the hydrobromide salt of the compound of Formula A in a solvent or a mixture of solvents.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the hydrobromide salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the hydrobromide salt of the compound of Formula A can be formed by adding hydrobromic acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent can be EtOH or THF.
  • the solvent can be EtOH or THF e.g. when the solid form is Form 18.
  • an antisolvent may be added.
  • the solvent can be EtOH and the antisolvent can be ethyl acetate, or the solvent can be THF and the antisolvent can be DCM e.g. when the solid form is Form 18.
  • Said process may also comprise trituration with an appropriate solvent.
  • the solvent can be MeCN, MEK and TBME (e.g.
  • the present invention also provides a process for the preparation of the malonate salt of the compound of Formula A, as described herein.
  • the present invention provides a process for the preparation of a crystalline solid form of the malonate salt of the compound of Formula A of the present invention (e.g. Forms 19, or 20), said process comprising the crystallisation of said solid form from a solution of the malonate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the malonate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the malonate salt of the compound of Formula A can be formed by adding malonic acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent can be THF, EtOH, or MeOH.
  • the solvent can be THF, e.g. when the solid form is Form 19.
  • the solvent can be EtOH or MeOH, e.g. when the solid form is Form 20.
  • an antisolvent may be added.
  • the solvent can be THF and the antisolvent can be DCM, e.g. when the solid form is Form 19.
  • the solvent can be EtOH and the antisolvent can be ethyl acetate, or the solvent can be MeOH and the antisolvent can be isopropyl acetate, DCM and MeCN, e.g. when the solid form is Form 20.
  • the present invention also provides a process for the preparation of the fumarate salt of the compound of Formula A, as described herein. Specifically, the present invention provides a process for the preparation of a crystalline solid form of the fumarate salt of the compound of Formula A of the present invention (e.g. Forms 21, 22, 23, 24, 25, or 26), said process comprising the crystallisation of said solid form from a solution of the fumarate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the fumarate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the fumarate salt of the compound of Formula A can be formed by adding fumaric acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent can be EtOH, MEK, THF, or MeOH.
  • the solvent can be EtOH or MEK, e.g. when the solid form is Form 21 or 22.
  • the solvent can be THF, e.g. when the solid form is Form 23.
  • the solvent can be EtOH, e.g. when the solid form is Form 24.
  • the solvent can be MeOH, e.g.
  • the solvent can be EtOH and the antisolvent can be ethyl acetate, or the solvent can be MEK and the antisolvent can be IPA, e.g. when the solid form is Form 21 or 22.
  • the solvent can be THF and the antisolvent can be DCM, e.g. when the solid form is Form 23.
  • the solvent can be EtOH and the antisolvent can be ethyl acetate, or the solvent can be MeOH and the antisolvent can be isopropyl acetate, DCM and MeCN, e.g. when the solid form is Form 24.
  • said process may comprise thermal cycling of a solid form of a fumarate salt of the compound of Formula A, e.g. when the solid Form is Form 24 or 26.
  • the present invention also provides a process for the preparation of the gentisate salt of the compound of Formula A, as described herein. Specifically, the present invention provides a process for the preparation of a crystalline solid form of the gentisate salt of the compound of Formula A of the present invention (e.g. Forms 27 or 28), said process comprising the crystallisation of said solid form from a solution of the gentisate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • said process may comprise the maturation or equilibration of said solid form from a suspension of the gentisate salt of the compound of Formula A in a solvent or a mixture of solvents.
  • the solution of the gentisate salt of the compound of Formula A can be formed by adding gentisic acid to a solution or suspension of the compound of Formula A in a solvent or a mixture of solvents.
  • the solvent can be EtOH or THF.
  • the solvent can be EtOH e.g. when the solid form is Form 27. .
  • the solvent can be THF e.g. when the solid form is Form 28.
  • an antisolvent may be added.
  • the solvent can be EtOH and the antisolvent can be ethyl acetate, e.g.
  • the solvent can be THF and the antisolvent can be DCM, e.g. when the solid form is Form 28. Said process may also comprise trituration with an appropriate solvent.
  • the solvent can be toluene and heptane (e.g. when the solid form is Form 28)
  • the processes of the present invention can also comprise the addition of crystalline seeds of the solid form of the invention.
  • seeds means a “seed crystal” which is a crystal of the target solid form. Adding “seeds” or “seeding” is a technique that can be used to expedite the preparation process and/or control the crystallisation of the intended solid form.
  • the solid forms of the present invention are inhibitors of FXIIa. They are therefore useful in the treatment of disease conditions for which FXIIa is a causative factor. Accordingly, the present invention provides the solid forms described herein for use in medicine. In a preferred embodiment, the crystalline solid form is Form 1. In an alternative preferred embodiment, the crystalline solid form is Form 10. The present invention also provides the use the solid forms described herein in the manufacture of a medicament for the treatment or prevention of a disease or condition in which FXIIa activity is implicated. In a preferred embodiment, the crystalline solid form is Form 1. In an alternative preferred embodiment, the crystalline solid form is Form 10.
  • the present invention also provides a method of treatment of a disease or condition in which FXIIa activity is implicated comprising administration to a subject in need thereof a therapeutically effective amount of a solid from as described herein.
  • the crystalline solid form is Form 1.
  • the crystalline solid form is Form 10.
  • FXIIa can mediate the conversion of plasma kallikrein from plasma prekallikrein. Plasma kallikrein can then cause the cleavage of high molecular weight kininogen to generate bradykinin, which is a potent inflammatory hormone. Inhibiting FXIIa has the potential to inhibit (or even prevent) plasma kallikrein production.
  • the disease or condition in which FXIIa activity is implicated can be a bradykinin-mediated angioedema.
  • the bradykinin-mediated angioedema can be non-hereditary.
  • the non-hereditary bradykinin-mediated angioedema can be selected from non-hereditary angioedema with normal C1 Inhibitor (AE-nC1 Inh), which can be environmental, hormonal, or drug-induced; acquired angioedema; anaphylaxis associated angioedema; angiotensin converting enzyme (ACE or ace) inhibitor-induced angioedema; dipeptidyl peptidase-4 inhibitor-induced angioedema; and tPA-induced angioedema (tissue plasminogen activator-induced angioedema).
  • AE-nC1 Inh normal C1 Inhibitor
  • the bradykinin-mediated angioedema can be hereditary angioedema (HAE), which is angioedema caused by an inherited dysfunction/fault/mutation.
  • HAE hereditary angioedema
  • Types of HAE that can be treated with solid forms according to the invention include HAE type 1, HAE type 2, and normal C1 inhibitor HAE (normal C1 Inh HAE).
  • HAE normal C1 Inh HAE
  • the disease or condition in which FXIIa activity is implicated can be selected from vascular hyperpermeability, stroke including ischemic stroke and haemorrhagic accidents; retinal edema; diabetic retinopathy; DME; retinal vein occlusion; and AMD. These conditions can also be bradykinin-mediated.
  • FXIIa can activate FXIa to cause a coagulation cascade. Thrombotic disorders are linked to this cascade. Thus, the disease or condition in which FXIIa activity is implicated can be a thrombotic disorder.
  • the thrombotic disorder can be thrombosis; thromboembolism caused by increased propensity of medical devices that come into contact with blood to clot blood; prothrombotic conditions such as disseminated intravascular coagulation (DIC), Venous thromboembolism (VTE), cancer associated thrombosis, complications caused by mechanical and bioprosthetic heart valves, complications caused by catheters, complications caused by ECMO, complications caused by LVAD, complications caused by dialysis, complications caused by CPB, sickle cell disease, joint arthroplasty, thrombosis induced to tPA, Paget-Schroetter syndrome and Budd-Chari syndrome; atherosclerosis; COVID-19; COVID-19 associated with SARS-CoV-2 infection; acute respiratory distress syndrome (ARDS); idiopathic pulmonary fibrosis (IPF); rheumatoid arthritis (RA); and cold-induced urticarial autoinflammatory syndrome.
  • DIC disseminated intravascular coagulation
  • VTE
  • the disease or condition in which FXIIa activity is implicated can be hereditary angioedema; COVID-19; COVID-19 associated with SARS-CoV- 2 infection; and idiopathic pulmonary fibrosis (IPF).
  • the disease or condition in which FXIIa activity is implicated can be COVID-19.
  • the disease or condition in which FXIIa activity is implicated can be COVID-19 associated with SARS-CoV-2 Infection.
  • the disease or condition in which FXIIa activity is implicated can be idiopathic pulmonary fibrosis (IPF). Surfaces of medical devices that come into contact with blood can cause thrombosis.
  • the solid forms of the present invention can be coated on the surfaces of devices that come into contact with blood to mitigate the risk of the device causing thrombosis. For instance, they can lower the propensity these devices to clot blood and therefore cause thrombosis.
  • devices that come into contact with blood include vascular grafts, stents, in dwelling catheters, external catheters, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems.
  • FXIIa is a causative factor
  • neuroinflammation neuroinflammatory/neurodegenerative disorders such as MS (multiple sclerosis); other neurodegenerative diseases such as Alzheimer’s disease, epilepsy and migraine; sepsis; bacterial sepsis; inflammation; vascular hyperpermeability; and anaphylaxis.
  • Brown adipose tissue (BAT) thermogenic activity can be mediated by the kallikrein-kinin system, and impaired BAT activity is associated with obesity and insulin resistance.
  • Inhibiting FXIIa has the potential to inhibit (or even prevent) BAT activity mediated by the kallikrein-kinin system.
  • the compounds (or pharmaceutically acceptable salts and/or solvates thereof) and pharmaceutical compositions of the invention can therefore treat disease conditions such as obesity and diabetes.
  • Factor XII inhibition is further implicated in the treatment of disease conditions such as kidney disease, renal fibrosis, glomerulosclerosis, renal scarring, ischemia/reperfusion injury in native or transplant kidneys, and acute kidney injury.
  • Brain glioblastoma growth and malignancy, as well as complications thereof including oedema and cognitive function may be beneficially affected by modulation of B1 and B2 kinin receptors, part of the kallikrein-kinin system, which are activated by bradykinin.
  • the disease or condition in which FXIIa activity is implicated can be brain glioblastoma growth and malignancy, as well as complications thereof including oedema and cognitive function.
  • Blocking the effect of bradykinin or inhibiting the activation of the kallikrein-kinin system has a therapeutic effect in treating and preventing the occurrence of intradialytic hypotension (IDH). Therefore, the disease or condition in which FXIIa activity is implicated can be intradialytic hypotension (IDH).
  • Combination Therapy The solid forms of the present invention may be administered alone or in combination with one or more other drugs. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the solid form(s) of the invention which may impart either a functional (i.e., drug release rate controlling) and/or a non-functional (i.e., processing aid or diluent) characteristic to the formulations.
  • a functional i.e., drug release rate controlling
  • a non-functional i.e., processing aid or diluent
  • the choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • the solid forms of the present invention may be administered in combination with other therapeutic agents.
  • Suitable combination therapies include any solid form of the present invention combined with one or more agents selected from agents that inhibit platelet-derived growth factor (PDGF), endothelial growth factor (VEGF), integrin alpha5beta1, steroids, other agents that inhibit FXIIa and other inhibitors of inflammation.
  • PDGF platelet-derived growth factor
  • VEGF endothelial growth factor
  • integrin alpha5beta1 steroids
  • FXIIa FXIIa and other inhibitors of inflammation.
  • Suitable combination therapies include a solid form of the invention combined with one or more agents selected from agents that treat HAE (as defined generally herein), for example bradykinin B2 antagonists such icatibant (Firazyr®); plasma kallikrein inhibitors such as ecallantide (Kalbitor®), lanadelumab (Takhzyro®) and berotralstat (ORLADEYOTM); or C1 esterase inhibitor such as Cinryze® and Haegarda® and Berinert® and Ruconest®.
  • agents that treat HAE as defined generally herein
  • bradykinin B2 antagonists such as icatibant (Firazyr®); plasma kallikrein inhibitors such as ecallantide (Kalbitor®), lanadelumab (Takhzyro®) and berotralstat (ORLADEYOTM); or C1 esterase inhibitor such as Cinryze® and Haegarda® and Berinert® and Ruconest®.
  • Suitable combination therapies include a solid form of the invention combined with one or more agents selected from agents that are antithrombotics (as outlined above), for example other Factor XIIa inhibitors, thrombin receptor antagonists, thrombin inhibitors, factor VIIa inhibitors, factor Xa inhibitors, factor XIa inhibitors, factor IXa inhibitors, adenosine diphosphate antiplatelet agents (e.g., P2Y12 antagonists), fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis) and aspirin) and platelet aggregation inhibitors.
  • agents that are antithrombotics as outlined above
  • agents that are antithrombotics for example other Factor XIIa inhibitors, thrombin receptor antagonists, thrombin inhibitors, factor VIIa inhibitors, factor Xa inhibitors, factor XIa inhibitors, factor IXa inhibitors, adenosine diphosphate
  • the solid forms of the present invention and said combination agents may exist in the same or different pharmaceutical compositions, and may be administered separately, sequentially or simultaneously.
  • the solid forms of the present invention can be administered in combination with laser treatment of the retina.
  • the combination of laser therapy with intravitreal injection of an inhibitor of VEGF for the treatment of diabetic macular edema is known (Elman M, Aiello L, Beck R, et al. “Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema” Ophthalmology.27 April 2010).
  • Pharmaceutical Compositions Pharmaceutical compositions suitable for the delivery of the solid form of the present invention and methods for their preparation will be readily apparent to those skilled in the art.
  • the present invention provides a pharmaceutical composition comprising a solid form or composition as described herein.
  • the pharmaceutical composition can comprise a crystalline solid form of the free base (Form 1) of the compound of Formula A, as hereinbefore defined, and a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the present invention also provides a pharmaceutical composition comprising a crystalline solid form of the mesylate salt (Form 10) of the compound of Formula A, as hereinbefore defined, and a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the pharmaceutical compositions can be administered topically (e.g.
  • the pharmaceutical composition is in the form of a suspension, tablet, capsule, powder, granule or suppository.
  • the active ingredient can be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • the formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
  • Uses and/or methods involving the solid forms described herein The present invention provides the use of a solid form or composition as described herein, in a method of manufacturing a pharmaceutical composition.
  • the present invention also provides the pharmaceutical composition resulting from, obtainable from, and/or obtained by, this use.
  • the present invention also provides a method of manufacturing a pharmaceutical composition comprising mixing a solid form or composition as described herein with one or more pharmaceutically acceptable excipients.
  • the present invention also provides the pharmaceutical composition resulting from, obtainable from, and/or obtained by, this method.
  • the present invention also provides a method of processing a solid form or composition as described herein into a medicament.
  • the present invention also provides the medicament resulting from, obtainable from, and/or obtained by, this method.
  • Figure 1c TGA thermograph of Form A of the compound of Formula A.
  • Figure 1d DVS isotherm profile of Form A of the compound of Formula A.
  • Figure 1e Optical microscopy micrograph of Form A of the compound of Formula A.
  • Figure 2a X-ray powder diffraction pattern of Form 1 of the compound of Formula A.
  • Figure 2b DSC/TGA thermograph overlay of Form 1 of the compound of Formula A.
  • Figure 2c DVS isotherm profile of Form 1 of the compound of Formula A.
  • Figure 2d Optical microscopy of Form 1 of the compound of Formula A.
  • Figure 2e X-ray powder diffraction pattern of Form 1 of the compound of Formula A post-storage at 40°C/75%RH for 2 weeks compared to input material Form 1.
  • Figure 3a X-ray powder diffraction pattern of Form 2 of the compound of Formula A.
  • Figure 3b DSC/TGA thermograph overlay of Form 2 of the compound of Formula A.
  • Figure 4a X-ray powder diffraction pattern of Form 3 of the compound of Formula A.
  • Figure 4b DSC/TGA thermograph overlay of Form 3 of the compound of Formula A.
  • Figure 5a X-ray powder diffraction pattern of Form 4 of the compound of Formula A.
  • Figure 5b DSC thermograph of Form 4 of the compound of Formula A.
  • Figure 6a X-ray powder diffraction pattern of Form 5 of the compound of Formula A.
  • Figure 6b DSC/TGA thermograph overlay of Form 5 of the compound of Formula A.
  • Figure 7a X-ray powder diffraction pattern of Form 6 of the compound of Formula A.
  • Figure 7b DSC thermograph of Form 6 of the compound of Formula A.
  • Figure 8a X-ray powder diffraction pattern of Form 7 of the compound of Formula A.
  • Figure 8b DSC/TGA thermograph overlay of Form 7 of the compound of Formula A.
  • Figure 9a X-ray powder diffraction pattern of Form 8 of the compound of Formula A.
  • Figure 9b DSC thermograph of Form 8 of the compound of Formula A.
  • Figure 9c TGA thermograph of Form 8 of the compound of Formula A.
  • Figure 10a X-ray powder diffraction pattern of Form 9 of the compound of Formula A.
  • Figure 10b DSC/TGA thermograph overlay of Form 9 of the compound of Formula A.
  • Figure 11a X-ray powder diffraction pattern of Form 10 of the compound of Formula A.
  • Figure 11b DSC/TGA thermograph overlay of Form 10 of the compound of Formula A.
  • Figure 11c DVS isotherm profile of Form 10 of the compound of Formula A.
  • Figure 11d Optical microscopy image of Form 10 of the compound of Formula A.
  • Figure 12a X-ray powder diffraction pattern of Form 11 of the compound of Formula A isolated from EtOH (top) and THF (bottom).
  • Figure 12b DSC/TGA thermograph overlay of Form 11 of the compound of Formula A.
  • Figure 13a X-ray powder diffraction pattern of Form 12 of the compound of Formula A.
  • Figure 13b DSC/TGA thermograph overlay of Form 12 of the compound of Formula A.
  • Figure 14a X-ray powder diffraction pattern of Form 13 of the compound of Formula A.
  • Figure 14b DSC/TGA thermograph overlay of Form 13 of the compound of Formula A.
  • Figure 15a X-ray powder diffraction pattern of Form 14 of the compound of Formula A.
  • Figure 15b DSC/TGA thermograph overlay of Form 14 of the compound of Formula A.
  • Figure 16a X-ray powder diffraction pattern of Form 15 of the compound of Formula A.
  • Figure 16b DSC/TGA thermograph overlay of Form 15 of the compound of Formula A.
  • Figure 17a X-ray powder diffraction pattern of Form 16 of the compound of Formula A.
  • Figure 17b DSC/TGA thermograph overlay of Form 16 of the compound of Formula A.
  • Figure 18a X-ray powder diffraction pattern of Form 17 of the compound of Formula A.
  • Figure 18b DSC/TGA thermograph overlay of Form 17 of the compound of Formula A.
  • Figure 19a X-ray powder diffraction pattern of Form 18 of the compound of Formula A isolated from EtOH (top) and THF (bottom).
  • Figure 19b DSC/TGA thermograph overlay of Form 18 of the compound of Formula A.
  • Figure 20a X-ray powder diffraction pattern of Form 19 of the compound of Formula A.
  • Figure 20b DSC/TGA thermograph overlay of Form 19 of the compound of Formula A.
  • Figure 21a X-ray powder diffraction pattern of Form 20 of the compound of Formula A.
  • Figure 21b DSC/TGA thermograph overlay of Form 20 of the compound of Formula A.
  • Figure 22a X-ray powder diffraction pattern of Form 21 of the compound of Formula A.
  • Figure 22b DSC/TGA thermograph overlay of Form 21 of the compound of Formula A.
  • Figure 23a X-ray powder diffraction pattern of Form 22 of the compound of Formula A.
  • Figure 23b DSC thermograph of Form 22 of the compound of Formula A.
  • Figure 24a X-ray powder diffraction pattern of Form 23 of the compound of Formula A.
  • Figure 24b DSC/TGA thermograph overlay of Form 23 of the compound of Formula A.
  • Figure 25a X-ray powder diffraction pattern of Form 24 of the compound of Formula A.
  • Figure 25b DSC thermograph of Form 24 of the compound of Formula A.
  • Figure 26a X-ray powder diffraction pattern of Form 25 of the compound of Formula A.
  • Figure 26b DSC thermograph of Form 25 of the compound of Formula A.
  • Figure 27a X-ray powder diffraction pattern of Form 26 of the compound of Formula A.
  • Figure 27b DSC thermograph of Form 26 of the compound of Formula A.
  • Figure 28a X-ray powder diffraction pattern of Form 27 of the compound of Formula A.
  • Figure 28b DSC/TGA thermograph overlay of Form 27 of the compound of Formula A.
  • Figure 29a X-ray powder diffraction pattern of Form 28 of the compound of Formula A.
  • Figure 29b DSC thermograph of Form 28 of the compound of Formula A.
  • the invention is illustrated by the following non-limiting examples. Abbreviations and definitions used throughout the entire disclosure include those as follows: All reactions were carried out under an atmosphere of nitrogen unless specified otherwise. Instruments and Methods References to the use of microwave, a microwave reactor, microwave heating and microwave irradiation all refer to the use of a CEM Discover Microwave Reactor. 1 H NMR spectra were recorded on a JEOL ECX 400MHz spectrometer or a Bruker (500MHz or 400MHz) spectrometer and reported as chemical shift (ppm).
  • Molecular ions were obtained using LCMS with appropriate conditions selected from ⁇ Chromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient 10% to 90% 0.1% HCO2H/MeCN into 0.1% HCO2H/H2O over 13 min, flow rate 1.5 mL/min; ⁇ Agilent, X-Select, acidic, 5-95% MeCN/water over 4 min.
  • LCMS Waters Acquity UPLC, C18, Waters X-Bridge UPLC C18, 1.7 ⁇ m, 2.1x30mm, Basic (0.1% Ammonium Bicarbonate) 3 min method; ⁇ LCMS (Agilent, X-Select, Waters X-Select C18, 2.5 ⁇ m, 4.6x30 mm, Acidic 4 min method, 95-5 MeCN/water); ⁇ LCMS (Agilent, Basic, Waters X-Bridge C18, 2.5 ⁇ m, 4.6x30 mm, Basic 4 min method, 5-95 MeCN/water; ⁇ Acquity UPLC BEH C181.7 ⁇ M column, 50 x 2.1 mm, with a linear gradient 10% to 90% 0.1% HCO2H/MeCN into 0.1%
  • IUPAC chemical names were generated using automated software such as Lexichem’s automatic chemical naming from OpenEye Scientific Software, Inc, provided as a component of Dotmatics Studies Notebook.
  • automated software used for naming include ChemDraw (PerkinElmer) or the Chemaxon software provided as a component of MarvinSketch or as a component of the IDBS E- WorkBook.
  • X-Ray Power Diffraction X-Ray Powder Diffraction patterns were collected on a PANalytical diffractometer using Cu K ⁇ radiation (45kV, 40mA), ⁇ - ⁇ goniometer, focusing mirror, divergence slit (1/2’’), soller slits at both incident and divergent beam (4mm) and a PIXcel detector.
  • the software used for data collection was X’Pert Data Collector, version 2.2f and the data was presented using X’Pert Data Viewer, version 1.2d.
  • XRPD patterns were acquired under ambient conditions via a transmission foil sample stage (polyimide - Kapton, 12.7 ⁇ m thickness film) under ambient conditions using a PANalytical X’Pert PRO.
  • DSC Differential Scanning Calorimetry
  • TGA Thermo-Gravimetric Analysis
  • the instrument was calibrated using a certified weight and certified Alumel and Perkalloy for temperature. A predefined amount of the sample, 1-5mg, was loaded onto a pre-tared aluminium crucible and was heated at 20oC.min -1 from rt to 400oC. A nitrogen purge at 20ml.min -1 was maintained over the sample. Instrument control, data acquisition and analysis was performed with Pyris Software v11.1.1 revision H. TA Instruments Discovery TGA equipped with a 25 position auto-sampler. The instrument was calibrated using a certified weight and certified Alumel and Nickel for temperature. A predefined amount of the sample, ca.
  • the humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow of 250ml min -1 .
  • the instrument was verified for relative humidity content by measuring three calibrated Rotronic salt solutions (10 - 50 - 88%).
  • the weight change of the sample was monitored as a function of humidity by a microbalance (accuracy +/- 0.005 mg).
  • a defined amount of sample was placed in a tared mesh stainless steel basket under ambient conditions.
  • a full experimental cycle typically consisted of three scans (sorption, desorption and sorption) at a constant temperature (25oC) and 10% RH intervals over a 0 – 90% range (60 min for each humidity level). This type of experiment should demonstrate the ability of samples studied to absorb moisture (or not) over a set of well-determined humidity ranges.
  • Optical Microscopy examination was undertaken using an Olympus BX53M polarised light microscope and an Olympus DP23 digital video camera for image capture. A small amount of each sample was placed onto a glass slide and dispersed in oil where appropriate. The samples were viewed with appropriate magnification and various images recorded. The image scale bar was calibrated against an external graticule, 0.1mm/0.002mm DIV.
  • the mixture was stirred at rt for 2 h and heated to reflux for a further 20 h. After cooling to rt, the mixture was concentrated and acidified by addition of AcOH (7 mL). The crude material was passed over an SCX column and washed with MeOH (70 mL) before being eluted with 2.5M NH 3 in MeOH (100 mL). The product-containing eluent was concentrated, redissolved in DCM (10 mL) and Boc 2 O added (2.34 g, 10.7 mmol).
  • the reaction was heated at 150 °C in a CEM Microwave for 1 h.
  • the mixture was diluted with DCM (20 mL) and water (20 mL).
  • the aqueous layer was re- extracted with DCM (3 x 10 mL) and the combined organics were washed with brine (20 mL).
  • the organic layer was dried (Na 2 SO 4 ), filtered and concentrated to afford the crude product. Purification was performed by flash chromatography (Silica, 20-50% EtOAc in Pet ether) to afford the product (276 mg, 50% yield) as an oil.
  • N1-(2,4-Dimethoxybenzyl)isoquinoline-1,5-diamine A mixture of 5-bromo-N-(2,4-dimethoxybenzyl)isoquinolin-1-amine (4.00 g, 10.7 mmol), 2,2,2- trifluoroacetamide (1.82 g, 16.1 mmol), copper(I) iodide (204 mg, 1.07 mmol), K2CO3 (2.96 g, 21.4 mmol) and DMF (189 mg, 2.14 mmol) was taken up in anhydrous 1,4-dioxane (10.6 mL) and the mixture purged with N2 then heated to 75 °C for 24 h.
  • the crude product was loaded onto SCX with MeOH and washed with MeOH.
  • the product was eluted with 0.7M NH3 in MeOH and the eluent concentrated.
  • the crude product was purified by flash chromatography (Silica, 0-9% (0.7M NH3 in MeOH) in DCM) and the column fractions containing product were transferred to a bulk vial with DCM and concentrated on the rotary evaporator to afford the product (65 mg, 85%) as a solid.
  • Form A was found to be amorphous.
  • DSC/TGA The DSC thermograph of Form A of the compound of Formula A is shown in Figure 1b.
  • the TGA thermograph of Form A of the compound of Formula A is shown in Figure 1c.
  • the DSC thermograph was largely featureless which was typical of an amorphous solid.
  • the TGA thermograph showed a weight loss of 2.0% up to 300 °C prior to decomposition.
  • DVS A DVS isotherm profile of Form A of the compound of Formula A is shown in Figure 1d.
  • the DVS profile of Form A of the compound of Formula A showed the solid absorbed up to 6.4% water over the humidity range ( Figure 1d). This represented almost two molar equivalents of water.
  • Process for preparing the solid and/or salt forms of the invention Processes for the preparation of the crystalline solid forms of the free base of the compound of Formula A Form 1 50 mg of the amorphous form of the compound of Formula A was weighed into a crystallisation tube and charged with 5 volumes of solvent (TBME, 2-methyl THF, CPME, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetone, MIBK, anisole, toluene, chlorobenzene, cumene, heptane, or cyclohexane). The mixture was allowed to equilibrate at 25 °C for ⁇ 30 min before an additional 5 volumes was charged and allowed to further equilibrate.
  • solvent TBME, 2-methyl THF, CPME, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetone, MIBK, anisole, toluene, chlorobenz
  • the mixture was then heated to 40 °C and allowed to equilibrate for a further 30 min, before an additional 10 volumes was charged.
  • the mixture was then heated systemically up to 60 °C with a minimum of 30 min equilibration.
  • the mixture was thermally cycled between 60 °C and 25 °C over 48 h with a minimum of 1 hour at temperature during heating phases. Solid was isolated at two temperatures, at 25°C during the last cycle and at the elevated temperature 60°C. Any solutions were clarified to clean, hot tubes to deliver unbiased recrystallisation and solids were isolated either by cooling crystallisation or slow evaporation. All solids were dried at 45 °C in vacuo for 24 h ahead of analysis.
  • TBME - Alternative method 500mg of the compound of Formula A was charged to a round bottom flask and TBME (20 vols) was added. The mixture was seeded then equilibrated at rt overnight. The resulting solid was isolated by vacuum filtration and dried in vacuo at 45°C overnight ahead of analysis.
  • An XRPD of Form 1 of the compound of Formula A is shown in Figure 2a. Peak position table: 1 H NMR confirmed the form was a free base of the compound of Formula A.
  • DSC/TGA The DSC/TGA overlay thermograph of Form 1 of the compound of Formula A is shown in Figure 2b. The DSC thermograph of the solid contained a single melt endotherm at 217°C.
  • the TGA thermograph contains a weight loss of 1.2% prior to the thermal decomposition.
  • DVS A DVS isotherm profile of Form 1 of the compound of Formula A is shown in Figure 2c.
  • DVS assessment revealed the solid absorbed up to 1% water over the humidity range. The water uptake was reversible and was lost on the subsequent desorption cycle with minor hysteresis noted.
  • the XRPD analysis of the solid post DVS cycling confirmed the solid remained as Form 1.
  • the profile of the crystalline solid Form 1 of the compound of Formula A (Figure 2c) was improved to that of amorphous phase of the compound of Formula A which demonstrated hygroscopic behaviour ( Figure 1d).
  • Optical Microscopy An optical microscopy image of Form 1 of the compound of Formula A is shown in Figure 2d.
  • the mixtures were allowed to equilibrate at 25 °C for ⁇ 30 min before an additional 5 volumes was charged and allowed to further equilibrate.
  • the mixtures were then heated to 40 °C and allowed to equilibrate for a further 30 min, before an additional 10 volumes was charged.
  • the mixtures were then heated systemically up to 60 °C with a minimum of 30 min equilibration.
  • the mixtures were thermally cycled between 60 °C and 25 °C over 48 h with a minimum of 1 hour at temperature during heating phases. Solids were isolated at two temperatures, at 25°C during the last cycle and at the elevated temperature 60°C. Solutions were clarified to clean, hot tubes to deliver unbiased recrystallisation and solids were isolated by slow evaporation.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and THF (1.35 ml, 30 vol) was added to give a pale yellow solution.
  • the maleic acid stock solution was charged (1 equivalent) in one single aliquot. The mixture was equilibrated for 18 h at rt. Where a suspension did not form an anti-solvent (DCM) was added at rt followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation. Ethanol – Alternative method A stock solution of maleic acid was prepared as a 1M solution in EtOH.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and EtOH (1.8 ml, 40 vol) was added to give a hazy solution.
  • EtOH 1.8 ml, 40 vol
  • the maleic acid stock solution was charged (1 equivalent) in one single aliquot at room temperature.
  • the mixture was equilibrated for 18 h. Where a suspension did not form an anti-solvent (EtOAc) was added at rt followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation.
  • Methanol - Alternative method A 1M stock solution of maleic acid in MeOH was prepared.
  • the compound of Formula A (50 mg) was weighed into a crystallisation tube and charged with 5 volumes of MeOH. The solution was then heated to 50 °C and allowed to equilibrate for 1 hour. The maleic acid solution (1 eq) was added in a single charge. The solution was allowed to equilibrate for a further hour at 50 °C before being cooled to rt and equilibrated for 24 h. The solid was isolated in vacuo and dried at 45 °C ahead of analysis. An XRPD of Form 3 of the compound of Formula A is shown in Figure 4a. 1 H NMR confirmed formation of the maleate salt with mono stoichiometry, with an indicative peak for maleic acid at 6.00 ppm integrating to 2 protons.
  • the DSC/TGA overlay thermograph of Form 3 of the compound of Formula A is shown in Figure 4b.
  • the DSC thermograph contained a discrete main melt endotherm at 223 °C, with the corresponding TGA showing a mass loss of 11.6% from 200 °C to 250 °C which is associated with the main melt endotherm. A mass loss of 2.2% was recorded prior to the solid melting.
  • Hydrochloride Salts Form 4 A 1M stock solution of hydrochloric acid in MeOH was prepared. The compound of Formula A (50 mg) was weighed into a crystallisation tube and charged with 5 volumes of MeOH. The solution was then heated to 50 °C and allowed to equilibrate for 1 hour.
  • Form 5 A stock solution of hydrochloric acid was prepared as a 1M solution in EtOH.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and THF (1.35 ml, 30 vol) was added to give a pale yellow solution.
  • the hydrochloric acid stock solution was charged (1 equivalent) in one single aliquot.
  • the mixture was equilibrated for 18 h at rt. Where a suspension did not form an anti-solvent (DCM) was added at rt followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation.
  • An XRPD of Form 5 of the compound of Formula A is shown in Figure 6a.
  • DSC/TGA The DSC/TGA overlay thermograph of Form 5 of the compound of Formula A is shown in Figure 6b.
  • the DSC thermograph contained a broad melt endotherm at 178°C with the corresponding TGA showing a mass loss of 9.7% from 115°C to 190°C. An exotherm was present in the thermograph at 235°C.
  • the NMR spectrum of the HCl salt isolated from THF showed ⁇ 7% of THF present which accounts for the majority of the mass loss in the TGA thermograph.
  • the large endotherm in the DSC thermograph may have related to the loss of THF and therefore may not have represented the true melt of the solid.
  • Various samples of Form 5 of the compound of Formula A were formed during screening with different levels of residual solvent. The mass loss shown in the TGA of each sample was consistently ⁇ 10% from 115°C to 190°C.
  • Tosylate Salts Form 6 THF A stock solution of p-toluene sulfonic acid was prepared as a 1M solution in EtOH. The compound of Formula A (45 mg) was charged to a crystallisation tube and THF (1.35 ml, 30 vol) was added to give a pale yellow solution.
  • the DSC thermograph contained a broad endotherm at 159°C followed by an exotherm at 175°C ahead of the main melt endotherm at 232°C.
  • Form 7 A 1M stock solution of p-toluene sulfonic acid in EtOH was prepared.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and ethanol (1.8 ml, 40 vol) was added to give a hazy solution.
  • the mixture was heated using a heat gun to form a solution and allowed to cool to rt.
  • the p-toluene sulfonic acid stock solution was charged (1 equivalent) in one single aliquot at room temperature.
  • the mixture was equilibrated for 18 h.
  • the solvent was removed by a steady stream of nitrogen.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and MEK (1.35 ml, 30 vol) added to give a pale yellow solution.
  • the p-toluene sulfonic acid was charged (1 equivalent) in one single aliquot at room temperature.
  • the mixture was equilibrated for 18 h. Where a suspension did not form, an anti-solvent (IPA) was added at rt followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation.
  • Alternative method The compound of Formula A (500mg) was charged to a round bottom flask and MEK (30 vols) was added.
  • Form 9 Form 7 of the compound of Formula A (20mg) was charged to a crystallisation tube and toluene was added (20 vols, 0.4 mL). The temperature was increased to 50°C and the mixture was equilibrated for 2 h then cooled to rt and equilibrated overnight. The mixture was heated to 50°C and equilibrated for 6 h then cooled to rt and isolated by vacuum filtration. Solids were dried in vacuo at 45°C overnight ahead of analysis. An XRPD of Form 9 of the compound of Formula A is shown in Figure 10a. 1 H NMR analysis confirmed mono stoichiometry. DSC/TGA The DSC/TGA overlay thermograph of Form 9 of the compound of Formula A is shown in Figure 10b.
  • the DSC thermograph contained a broad endotherm at 145°C followed immediately by an exotherm at 150°C.
  • the main melt endotherm was present at 215°C.
  • the first broad endotherm corresponds with a mass loss in the TGA thermograph of 13% from 25°C to 135°C.
  • Mesylate Salt Form 10 The compound of Formula A (1.37g) was weighed into a round bottom flask and THF (41mL, 30 vols) was added. A light orange solution formed. Methane sulfonic acid (1M stock solution in THF, 1eq, 2.92 mL) was added as a single charge and a suspension formed immediately. The mixture was equilibrated at rt overnight and solid was isolated by vacuum filtration.
  • the DSC thermograph contained a main melt endotherm at 223°C followed immediately by an exothermic event.
  • the TGA thermograph showed a weight loss of 1.6% from 25°C to 200°C. This mass loss was likely to relate to water loss given there was minimal residual solvent in the 1 H NMR spectra of the salt.
  • DVS A DVS isotherm profile of Form 10 of the compound of Formula A is shown in Figure 11c.
  • DVS analysis showed a steady decrease in mass as the humidity dropped from ambient to 0% relative humidity in the initial desorption cycle. As the humidity increased there was a steady increase in mass up to a maximum of 1.0%. The mass gain was considered to be surface water and was reversible in the subsequent desorption cycle with minor hysteresis noted.
  • FIG. 11d An optical microscopy image of Form 10 of the compound of Formula A is shown in Figure 11d.
  • a sample of Form 10 of the compound of Formula 1 (30mg) was charged to a vial which was then placed in a stability cabinet at 40°C and 75% humidity loosely lidded. The sample was left for 2 weeks with analysis collected following 1 and 2 weeks storage.
  • Form 10 of the compound of Formula A was found to be stable with respect to crystalline form after 2 weeks under accelerated storage conditions. Chemical purity by HPLC also remained unchanged.
  • Malate salts Form 11 THF A stock solution of (-)-(L)-Malic acid was prepared as a 1M solution in EtOH.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and EtOH (1.8 ml, 40 vol) was added to give a hazy solution. The mixture was heated using a heat gun to form a solution and allowed to cool to rt. The (-)-(L)-Malic acid stock solution was charged (1 equivalent) in one single aliquot at room temperature. The mixture was equilibrated for 18 h. Where a suspension did not form an anti-solvent (EtOAc) was added at rt followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation. An XRPD of Form 11 of the compound of Formula A is shown in Figure 12a.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and EtOH (1.8 ml, 40 vol) added. The temperature was increased to 50°C to give a pale yellow solution.
  • the (-)-(L)-Malic acid was charged (1 equivalent) in one single aliquot.
  • the mixture was equilibrated for 5 h at 50°C then cooled to room temperature and equilibrated for 18 h.
  • the mixture was subjected to heat cycled maturation (6 h at 50°C followed by 18 h at rt, repeated 3 times). Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation.
  • the DSC thermograph contained a single melt endotherm at 246°C.
  • the TGA thermograph showed a weight loss of 0.9% prior to the thermal decomposition.
  • Tartrate Salt Form 13 A stock solution of L-tartaric acid was prepared as a 0.5M solution in EtOH. The compound of Formula A (45 mg) was charged to a crystallisation tube and EtOH (1.8 ml, 40 vol) added. The temperature was increased to 50°C to give a pale yellow solution. L-tartaric acid was charged (1 equivalent) in one single aliquot. The mixture was equilibrated for 5 h at 50°C then cooled to room temperature and equilibrated for 18 h.
  • Ethanol – alternative method A stock solution of succinic acid was prepared as a 0.25M solution in EtOH.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and EtOH (1.8 ml, 40 vol) was added to give a hazy solution.
  • the mixture was heated using a heat gun to form a solution and allowed to cool to rt.
  • the succinic acid stock solution was charged (1 equivalent) in one single aliquot at room temperature.
  • the mixture was equilibrated for 18 h. Where a suspension did not form an anti-solvent (EtOAc) was added at rt followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation.
  • FIG. 15a An XRPD of Form 14 of the compound of Formula A is shown in Figure 15a.
  • 1 H NMR data confirmed the formation of a mono succinate salt.
  • DSC/TGA The DSC/TGA overlay thermograph of Form 14 of the compound of Formula A is shown in Figure 15b.
  • the DSC thermograph had a discrete main melt at 219 °C, and the corresponding TGA showed a mass loss of 11.6% from 200 °C to 260 °C which was associated with the main melt endotherm. A mass loss of 2.2% was recorded prior to the solid melting which appeared to relate to the loss of EtOH which was shown to be at a similar level in the corresponding NMR spectrum.
  • Form 15 A stock solution of succinic acid was prepared as a 0.25M solution in EtOH.
  • the DSC/TGA overlay thermograph of Form 15 of the compound of Formula A is shown in Figure 16b.
  • the DSC thermograph had a discrete main melt at 217 °C, and the corresponding TGA showed a mass loss of 11.8% from 200 °C to 260 °C which was associated with the main melt endotherm.
  • An additional endotherm is present at 204°C followed by a sharp exotherm at 207°C.
  • This main melt event corresponded with that previously noted for Form 14 which was seen to melt at 219°C.
  • a similar shoulder to the main endotherm was present as was observed for Form 14.
  • a mass loss of 1.2% was recorded prior to the solid melting.
  • Form 16 A stock solution of succinic acid was prepared as a 0.25M solution in EtOH.
  • the DSC/TGA overlay thermograph of Form 16 of the compound of Formula A is shown in Figure 17b.
  • the DSC thermograph of Form 16 contained 3 broad endotherms at 92°C, 125°C and 230°C, with the corresponding TGA showing a mass loss of 3.1% from 25°C to 100°C followed by a loss of 1.1% from 100°C to 150°C and a loss of 5.3% from 150°C to 270°C.
  • the profile indicates likely hydration with only minimal residual solvent present by NMR.
  • Phosphate Salts Form 17 A stock solution of phosphoric acid was prepared as a 1M solution in EtOH.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and EtOH (1.8 ml, 40 vol) was added to give a hazy solution. The mixture was heated using a heat gun to form a solution and allowed to cool to rt. The phosphoric acid stock solution was charged (1 equivalent) in one single aliquot at room temperature. The mixture was equilibrated for 18 h. Where a suspension did not form an anti-solvent (EtOAc) was added at rt followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation. An XRPD of Form 17 of the compound of Formula A is shown in Figure 18a.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and THF (1.35 ml, 30 vol) was added to give a pale yellow solution.
  • the hydrobromic acid stock solution was charged (1 equivalent) in one single aliquot. The mixture was equilibrated for 18 h at rt. Where a suspension did not form an anti-solvent (DCM) was added at rt followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation. Ethanol – alternative method A stock solution of hydrobromic acid was prepared as a 1M solution in EtOH.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and EtOH (1.8 ml, 40 vol) was added to give a hazy solution.
  • EtOH 1.8 ml, 40 vol
  • the hydrobromic acid stock solution was charged (1 equivalent) in one single aliquot at room temperature.
  • the mixture was equilibrated for 18 h.
  • the solvent was removed by a steady stream of nitrogen. Repeat scratching and trituration of the resulting residue with MeCN, MEK and TBME was followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation.
  • An XRPD of Form 18 of the compound of Formula A is shown in Figure 19a.
  • the DSC/TGA overlay thermograph of Form 19 of the compound of Formula A is shown in Figure 20b.
  • the DSC thermograph contained an endotherm at 159°C and the corresponding TGA showed a mass loss of 22.7% from 130°C to 210°C associated with the main melt endotherm.
  • Form 20 Ethanol A stock solution of malonic acid was prepared as a 1M solution in EtOH.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and EtOH (1.8 ml, 40 vol) was added to give a hazy solution.
  • the mixture was heated using a heat gun to form a solution and allowed to cool to rt.
  • the malonic acid stock solution was charged (1 equivalent) in one single aliquot at room temperature.
  • Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation.
  • MEK – alternative method A stock solution of fumaric acid was prepared as a 0.25M solution in EtOH. The compound of Formula A (45 mg) was charged to a crystallisation tube and MEK (1.35 ml, 30 vol) was added to give a pale yellow solution. The fumaric acid was charged (1 equivalent) in one single aliquot at room temperature. The mixture was equilibrated for 18 h. Where a suspension did not form an anti-solvent (IPA) was added at rt followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation.
  • IPA anti-solvent
  • FIG. 23a An XRPD of Form 22 of the compound of Formula A is shown in Figure 23a.
  • DSC/TGA The DSC thermograph of Form 22 of the compound of Formula A is shown in Figure 23b.
  • the DSC thermograph contained a single melt endotherm at 252°C.
  • Form 23 A stock solution of fumaric acid was prepared as a 0.25M solution in EtOH.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and THF (1.35 ml, 30 vol) was added to give a pale yellow solution.
  • the fumaric acid stock solution was charged (1 equivalent) in one single aliquot. The mixture was equilibrated for 18 h at rt.
  • FIG. 25a An XRPD of Form 24 of the compound of Formula A is shown in Figure 25a. 1 H NMR confirmed hemi stoichiometry. DSC he DSC thermograph of Form 24 of the compound of Formula A is shown in Figure 25b. The DSC thermograph contained a single melt endotherm at 250°C. Form 25 A stock solution of fumaric acid was prepared as a 0.25M solution in EtOH. The compound of Formula A (45 mg) was charged to a crystallisation tube and MeOH (0.9 ml, 20 vol) added to give a pale yellow solution. The fumaric acid was charged (0.5 equivalents) in one single aliquot at room temperature. The mixture was equilibrated for 18 h.
  • Form 28 A stock solution of gentisic acid was prepared as a 1M solution in EtOH.
  • the compound of Formula A (45 mg) was charged to a crystallisation tube and THF (1.35 ml, 30 vol) was added to give a pale yellow solution.
  • the gentisic acid stock solution was charged (1 equivalent) in one single aliquot.
  • the mixture was equilibrated for 18 h at rt.
  • the solvent was removed by a steady stream of nitrogen. Repeat scratching and trituration of the resulting residue with toluene and heptane was followed by equilibration. Isolated solid was dried in vacuo at 45°C for 18 h ahead of characterisation.
  • An XRPD of Form 28 of the compound of Formula A is shown in Figure 29a.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouvelles formes solides de l'inhibiteur du facteur XIIa (FXIIa) (R)-N5-((4-méthyl-6-(6-méthyl-3-(trifluorométhyl)-5,6-dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-3-yl)méthyl)isoquinoline-1,5-diamine et ses sels.
PCT/GB2024/051019 2023-04-20 2024-04-19 Formes solides d'un inhibiteur d'enzyme et sels associés Pending WO2024218503A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363497388P 2023-04-20 2023-04-20
US63/497,388 2023-04-20

Publications (1)

Publication Number Publication Date
WO2024218503A1 true WO2024218503A1 (fr) 2024-10-24

Family

ID=90924837

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2024/051019 Pending WO2024218503A1 (fr) 2023-04-20 2024-04-19 Formes solides d'un inhibiteur d'enzyme et sels associés

Country Status (1)

Country Link
WO (1) WO2024218503A1 (fr)

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2281885A1 (fr) 2003-08-27 2011-02-09 Ophthotech Corporation Combination thérapeutique pour le traitement des troubles oculaires néovasculaires
WO2012120128A1 (fr) 2011-03-09 2012-09-13 Csl Behring Gmbh Inhibiteurs du facteur xii destinés à être administrés avec des procédures médicales comprenant le contact avec des surfaces artificielles
WO2017123518A1 (fr) 2016-01-11 2017-07-20 The Rockefeller University Immunomodulateurs d'aminotriazole pour traiter des maladies auto-immunes
WO2017205296A1 (fr) 2016-05-23 2017-11-30 The Rockefeller University Immunomodulateurs à base d'aminocylindazole pour le traitement de maladies auto-immunes
WO2018093695A1 (fr) 2016-11-18 2018-05-24 Merck Sharp & Dohme Corp. Inhibiteurs du facteur xiia
WO2018093716A1 (fr) 2016-11-18 2018-05-24 Merck Sharp & Dohme Corp. Inhibiteurs de facteur xiia
WO2019108565A1 (fr) 2017-11-29 2019-06-06 The Rockefeller University Immunomodulateurs à base de pyranopyrazole et de pyrazolopyridine pour le traitement de maladies auto-immunes
WO2019113642A1 (fr) 2017-12-15 2019-06-20 Csl Limited Utilisation d'un inhibiteur de fxiia dans le traitement d'une fibrose rénale et/ou d'une maladie rénale chronique
WO2019186164A1 (fr) 2018-03-29 2019-10-03 University Of Leeds Inhibiteurs du facteur xiia
WO2019211585A1 (fr) 2018-04-30 2019-11-07 University Of Leeds Inhibiteurs du facteur xiia
WO2022118016A2 (fr) 2020-12-01 2022-06-09 Kalvista Pharmaceuticals Limited Inhibiteurs enzymatiques

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2281885A1 (fr) 2003-08-27 2011-02-09 Ophthotech Corporation Combination thérapeutique pour le traitement des troubles oculaires néovasculaires
WO2012120128A1 (fr) 2011-03-09 2012-09-13 Csl Behring Gmbh Inhibiteurs du facteur xii destinés à être administrés avec des procédures médicales comprenant le contact avec des surfaces artificielles
WO2017123518A1 (fr) 2016-01-11 2017-07-20 The Rockefeller University Immunomodulateurs d'aminotriazole pour traiter des maladies auto-immunes
WO2017205296A1 (fr) 2016-05-23 2017-11-30 The Rockefeller University Immunomodulateurs à base d'aminocylindazole pour le traitement de maladies auto-immunes
WO2018093695A1 (fr) 2016-11-18 2018-05-24 Merck Sharp & Dohme Corp. Inhibiteurs du facteur xiia
WO2018093716A1 (fr) 2016-11-18 2018-05-24 Merck Sharp & Dohme Corp. Inhibiteurs de facteur xiia
WO2019108565A1 (fr) 2017-11-29 2019-06-06 The Rockefeller University Immunomodulateurs à base de pyranopyrazole et de pyrazolopyridine pour le traitement de maladies auto-immunes
WO2019113642A1 (fr) 2017-12-15 2019-06-20 Csl Limited Utilisation d'un inhibiteur de fxiia dans le traitement d'une fibrose rénale et/ou d'une maladie rénale chronique
WO2019186164A1 (fr) 2018-03-29 2019-10-03 University Of Leeds Inhibiteurs du facteur xiia
WO2019211585A1 (fr) 2018-04-30 2019-11-07 University Of Leeds Inhibiteurs du facteur xiia
WO2022118016A2 (fr) 2020-12-01 2022-06-09 Kalvista Pharmaceuticals Limited Inhibiteurs enzymatiques

Non-Patent Citations (84)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING COMPANY
A DEMENTIEV ET AL.: "Structures of human plasma βfactor Xlla cocrystallized with potent inhibitors", BLOOD ADVANCES, vol. 2, no. 5, 2018, pages 549 - 558
ABDALLAH ET AL., J BIOL CHEM., vol. 285, no. 45, 5 November 2010 (2010-11-05), pages 35206 - 15
ABID ET AL., J BIOL CHEM., vol. 284, no. 37, 11 September 2009 (2009-09-11), pages 24715 - 24
B. K. HAMAD ET AL.: "Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation", JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol. 15, pages 1818 - 1828
BAERISWYL ET AL., ACS CHEM. BIOL., vol. 10, no. 8, 2015, pages 1861
BARBIERI ET AL., J PHARMACOL EXP THER., vol. 360, no. 3, March 2017 (2017-03-01), pages 466 - 475
BAS ET AL., N ENGL J MED, 2015
BENDER ET AL., FRONT IMMUNOL., vol. 8, 15 September 2017 (2017-09-15), pages 1115
BERNSTEIN, J.: "Polymorphism in Molecular Crystals", 2002, OXFORD UNIVERSITY PRESS
BJBRKQVIST ET AL., J CLIN INVEST., vol. 125, no. 8, 3 August 2015 (2015-08-03), pages 3132 - 46
BOUCKAERT ET AL., EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 110, 2016, pages 181
BYRN, S.R.PFEIFFER, R.R.STOWELL, J.G.: "Handbook of Pharmaceutical Salts; Properties, Selection and Use", 1999, VERLAG HELVETICA CHIMICA ACTA
CLERMONT ET AL., ARVO TALK, 2019
CLERMONT ET AL., INVEST OPHTHALMOL VIS SCI., vol. 57, no. 6, 1 May 2016 (2016-05-01), pages 2390 - 9
CRAIG ET AL., THE LANCET., vol. 401, no. 10382, 2023, pages 1079 - 1090, Retrieved from the Internet <URL:https://www.clinicaltrials.gov/ct2/show/NCT04656418>
DAVIE ET AL., SCIENCE, vol. 145, no. 3638, 18 September 1964 (1964-09-18), pages 1310 - 2
DE MAAT ET AL., J ALLERGY CLIN IMMUNOL., vol. 138, no. 5, November 2016 (2016-11-01), pages 1414 - 1423,e9
DIDIASOVA ET AL., CELL SIGNAL., vol. 51, November 2018 (2018-11-01), pages 257 - 265
DIESTRO ET AL., J STROKE CEREBROVASC DIS., vol. 28, no. 5, May 2019 (2019-05-01), pages e44 - e45
ELMAN MAIELLO LBECK R ET AL.: "Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema", OPHTHALMOLOGY, 27 April 2010 (2010-04-27)
FROHLICH ET AL., STROKE, 11 June 2019 (2019-06-11)
GAMBOA ET AL.: "Bradykinin B receptor blockade and intradialytic hypotension", BMC NEPHROLOGY, vol. 24, 2023, pages 134, Retrieved from the Internet <URL:http://doi.org/10.1186/s12882-023-03192-4>
GAO ET AL., J PROTEOME RES., vol. 7, no. 6, June 2008 (2008-06-01), pages 2516 - 25
GAO ET AL., NAT MED., vol. 13, no. 2, 28 January 2007 (2007-01-28), pages 181 - 8
GBBEL ET AL., NAT COMMUN., vol. 7, 18 May 2016 (2016-05-18), pages 11626
GBBEL ET AL., PROC NATL ACAD SCI USA., vol. 116, no. 1, 2 January 2019 (2019-01-02), pages 271 - 276
GBBEL ET AL.: "The Coagulation Factors Fibrinogen, Thrombin, and Factor XII in Inflammatory Disorders-A Systematic Review", FRONT. IMMUNOL., 26 July 2018 (2018-07-26), Retrieved from the Internet <URL:https://doi.org/10.3389/fimmu.2018.01731>
GHEBREHIWET ET AL., IMMUNOL REV., vol. 274, no. 1, November 2016 (2016-11-01), pages 281 - 289
GHEBREHIWET ET AL., J EXP MED., vol. 153, no. 3, 1 March 1981 (1981-03-01), pages 665 - 76
GIARD ET AL., DERMATOLOGY., vol. 225, no. 1, 2012, pages 62 - 9
H. LIEBERMANL. LACHMAN: "Pharmaceutical Dosage Forms: Tablets", vol. 1, 1980, MARCEL DEKKER
HAN ET AL., JCI, 2002
HERMANRUD ET AL., BMJ CASE REP., 10 January 2017 (2017-01-10), pages bcr2016217802
HILL ET AL., NEUROLOGY, vol. 60, no. 9, 13 May 2003 (2003-05-13), pages 1525 - 7
HOPP ET AL., J NEUROINFLAMMATION., vol. 14, no. 1, 20 February 2017 (2017-02-20), pages 39
INVANOV ET AL., BLOOD, vol. 129, no. 11, 16 March 2017 (2017-03-16), pages 1527 - 1537
IRMSCHER ET AL., J INNATE IMMUN., vol. 10, no. 2, 2018, pages 94 - 105
JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, 2008, pages 589 - 602
KAPLAN ET AL., ADV IMMUNOL., vol. 121, 2014, pages 41 - 89
KEDARISETTY ET AL., OTOLARYNGOL HEAD NECK SURG., 30 April 2019 (2019-04-30)
KIM ET AL., BASIC CLIN PHARMACOL TOXICOL., vol. 124, no. 1, January 2019 (2019-01-01), pages 115 - 122
KITA ET AL., DIABETES., vol. 64, no. 10, October 2015 (2015-10-01), pages 3588 - 99
KONINGS ET AL., THROMB RES., vol. 136, no. 2, August 2015 (2015-08-01), pages 474 - 80
KRUPKA ET AL., PLOS ONE., vol. 11, no. 1, 27 January 2016 (2016-01-27), pages e0146783
LARSSON MRAYZMAN VNOLTE MW ET AL.: "A factor Xlla inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk", SCI TRANSL MED., vol. 6, no. 222, 2014, pages 222ra17
LEIBFRIEDKOVARY, J PHARM PRACT, 2017
LEKOUBOU ET AL., NEUROL RES., vol. 36, no. 7, July 2014 (2014-07-01), pages 687 - 94
LEUNG ET AL., TRANSL STROKE RES., vol. 3, no. 3, September 2012 (2012-09-01), pages 381 - 9
LIU ET AL., BIOL CHEM., vol. 394, no. 3, March 2013 (2013-03-01), pages 319 - 28
LIU ET AL., NAT MED., vol. 17, no. 2, February 2011 (2011-02-01), pages 206 - 10
LONG ET AL., NANOTOXICOLOGY., vol. 10, no. 4, 2016, pages 501 - 11
M. PATHAK ET AL.: "Crystal structures of the recombinant β-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics", ACTA. CRYST., vol. D75, 2019, pages 1 - 14
MAAT ET AL., J THROMB HAEMOST., vol. 17, no. 1, January 2019 (2019-01-01), pages 183 - 194
MANSI ET AL., THE ASSOCIATION FOR THE PUBLICATION OF THE JOURNAL OF INTERNAL MEDICINE JOURNAL OF INTERNAL MEDICINE, vol. 277, 2014, pages 585 - 593
MCKENZIE ET AL.: "A phase I, first-in-human, randomized dose-escalation study of anti-activated factor XII monoclonal antibody garadacimab", CLIN TRANSL SCI., vol. 15, 2022, pages 626 - 637
MORRISON ET AL., J EXP MED., vol. 140, no. 3, 1 September 1974 (1974-09-01), pages 797 - 811
MURUGESAN ET AL., EXP EYE RES., vol. 186, 24 July 2019 (2019-07-24), pages 107744
NICOLETTI ET AL.: "Primary Role for Kinin B and B Receptors in Glioma Proliferation", MOL NEUROBIOL, vol. 54, 2017, pages 7869 - 7882, XP036362715, DOI: 10.1007/s12035-016-0265-9
P. M. FISCHER: "Design of Small-Molecule Active-Site Inhibitors of the S1A Family Proteases as Procoagulant and Anticoagulant Drugs", J. MED. CHEM., vol. 61, no. 9, 2018, pages 3799 - 3822, XP055641426, DOI: 10.1021/acs.jmedchem.7b00772
PEYROU ET AL.: "The kallikrein-kinin pathway as a mechanism for auto-control of brown adipose tissue activity", NATURE COMMUNICATIONS, vol. 11, 2020, pages 2132, Retrieved from the Internet <URL:https://doi.org/10.1038/s41467-020-16009-x>
PUY ET AL., J THROMB HAEMOST., vol. 11, no. 7, July 2013 (2013-07-01), pages 1341 - 52
RADCLIFFE ET AL., BLOOD., vol. 50, no. 4, October 1977 (1977-10-01), pages 611 - 7
RATHBUN, OXF MED CASE REPORTS., vol. 2019, no. 1, 24 January 2019 (2019-01-24)
RECKE ET AL., CLIN TRANSL ALLERGY, vol. 9, 14 February 2019 (2019-02-14), pages 9
REICHMAN ET AL., PHARMACOEPIDEMIOL DRUG SAF., vol. 26, no. 10, October 2017 (2017-10-01), pages 1190 - 1196
RENNE ET AL., J EXP MED., vol. 202, no. 2, 18 July 2005 (2005-07-18), pages 271 - 81
S. PATEL, RETINA, vol. 29, June 2009 (2009-06-01), pages S45 - 8
SALA-CUNILL ET AL., J ALLERGY CLIN IMMUNOL., vol. 135, no. 4, April 2015 (2015-04-01), pages 1031 - 43,e6
SCHEFFEL ET AL.: "Cold-induced urticarial autoinflammatory syndrome related to factor XII activation", NATURE COMMUNICATIONS VOLUME, vol. 11, no. 179, 2020
SCOTT ET AL., CURR DIABETES REV., vol. 14, no. 4, 2018, pages 327 - 333
SHATZEL ET AL., RES PRACT THROMB HAEMOST, vol. 4, no. 4, 15 May 2020 (2020-05-15), pages 500 - 505
SIMAO ET AL., BLOOD, vol. 129, no. 16, 20 April 2017 (2017-04-20), pages 2280 - 2290
SIMAO ET AL., BLOOD., vol. 129, no. 16, 20 April 2017 (2017-04-20), pages 2280 - 2290
SIMAO ET AL., FRONT MED (LAUSANNE)., vol. 4, 31 July 2017 (2017-07-31), pages 121
SIMBES ET AL., J NEUROCHEM., vol. 150, no. 3, August 2019 (2019-08-01), pages 296 - 311
STONE ET AL., IMMUNOL ALLERGY CLIN NORTH AM., vol. 37, no. 3, August 2017 (2017-08-01), pages 483 - 495
VAN DEN ELZEN ET AL., CLINIC REV ALLERG IMMUNOL, 2018
VERONEZ ET AL., FRONT MED (LAUSANNE, vol. 6, 21 February 2019 (2019-02-21), pages 28
WILBS ET AL., NAT COMMUN, vol. 11, 2020, pages 3890
WONG ET AL.: "CSL312, a Novel Anti-FXII Antibody, Blocks FXII-Induced IL-6 Production from Primary Non-Diseased and Idiopathic Pulmonary Fibrosis Fibroblasts", AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 201, 2020, pages A6363
WORM ET AL., ANN TRANSL MED., vol. 3, no. 17, October 2015 (2015-10-01), pages 247
WYGRECKA ET AL.: "Coagulation factor XII regulates inflammatory responses in human lungs", EUROPEAN RESPIRATORY JOURNAL 2017, vol. 50, pages PA339
ZAMOLODCHIKOV ET AL., PROC NATL ACAD SCI USA., vol. 112, no. 13, 31 March 2015 (2015-03-31), pages 4068 - 73

Similar Documents

Publication Publication Date Title
US20230203012A1 (en) Solid forms of a plasma kallikrein inhibitor and salts thereof
JP6937734B2 (ja) 第ｘｉａ因子阻害剤としてのピリミジノン
JP6785838B2 (ja) 新規な置換グリシン誘導のｆｘｉａ阻害剤
TWI586651B (zh) 作為因子ｘｉａ抑制劑之經取代四氫異喹啉化合物
JP6957516B2 (ja) カリクレインインヒビターとしての、ｎ−［（３−フルオロ−４−メトキシピリジン−２−イル）メチル］−３−（メトキシメチル）−１−（｛４−［（２−オキソピリジン−１−イル）メチル］フェニル｝メチル）ピラゾール−４−カルボキサミドの多形体
US10752607B2 (en) Polymorphs of N-[(6-cyano-2-fluoro)-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide as kallikrein inhibitors
SK172098A3 (en) New amidino derivatives and their use as thrombin inhibitors
AU2018374539A1 (en) Solid forms of a plasma kallikrein inhibitor and salts thereof
EP4017586A1 (fr) Inhibiteurs d&#39;enzymes
JP2019517461A (ja) Ｎ−［（２，６−ジフルオロ−３−メトキシフェニル）メチル］−３−（メトキシメチル）−１−（｛４−［（２−オキソピリジン−１−イル）メチル］フェニル｝メチル）ピラゾール−４−カルボキサミドの多形体
AU2019462140A1 (en) Enzyme inhibitors
AU2020331720A1 (en) Enzyme inhibitors
AU2020333222A1 (en) Enzyme inhibitors
WO2022175675A1 (fr) Inhibiteurs du facteur xiia
WO2024218503A1 (fr) Formes solides d&#39;un inhibiteur d&#39;enzyme et sels associés
EP4255900A2 (fr) Inhibiteurs enzymatiques
SA03240440B1 (ar) أملاح حمض مضافة مقبولة صيدلانيا من مركبات معينة من ميثوكسي methoxy وايثوكسي ethoxy اميدين amidine وعمليات الحصول عليها
Xing et al. Design, synthesis and biological evaluation of anthranilamide derivatives as potential factor Xa (fXa) inhibitors
WO2024038282A1 (fr) Dérivés de 2-aza- et 2-oxabicyclo[2.1.1]hexane utilisés comme inhibiteurs de l&#39;enzyme du facteur xiia
CN116829547A (zh) 因子XIIa抑制剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24723208

Country of ref document: EP

Kind code of ref document: A1