Treatment of stroke

Abstract

Disclosed is the compound of Formula (I), and pharmaceutical salts thereof, for use in the treatment of stroke (e.g. acute ischaemic stroke and haemorrhagic stroke) and post-stroke pain, wherein the compound is administered to a subject less than 6 hours from stroke onset. Also disclosed is the compound for use in preventing or reducing the risk of iatrogenic stroke and pharmaceutical compositions comprising the compound.

Description

TREATMENT OF STROKE

[0001] The present invention relates to a compound of Formula (I) as defined herein, or a pharmaceutical salt thereof, for use in the treatment of stroke (e.g. acute ischaemic stroke and haemorrhagic stroke) and post-stroke pain, wherein the compound is administered to a subject less than 6 hours from stroke onset. The compound is also useful in preventing or reducing the risk of iatrogenic stroke.BACKGROUND OF THE INVENTION

[0002] Fifteen million people suffer from a stroke annually worldwide. Five million of these die and another five million are left with permanent disability.1Despite decades of work, the only currently approved acute pharmacological treatment for ischaemic stroke is thrombolysis with recombinant tissue plasminogen activator (t-PA), but the benefits of t-PA are limited by a short treatment time window, low rates of reperfusion, the potential for haemorrhagic transformation of injured and infarcted brain, and direct neurotoxicity of t-PA.2Less than 10% of acute stroke patients receive t-PA primarily due to the short therapeutic time window and contra-indications such as concurrent anticoagulant use or recent surgery.1 2An urgent need therefore exists for new stroke therapies.

[0003] Cerebral ischaemia and haemorrhage initiate and propagate a cascade of detrimental pathways that ultimately lead to cellular injury and death. Extensive pre-clinical and clinical data suggest that matrix metalloproteinases (MMPs) play a central role in mediating and promoting brain injury in stroke.2-8

[0004] MMPs form a multi-gene family of zinc-dependent endopeptidases of over 25 enzymes that are secreted by various cell types. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, growth factors, growth factor-binding proteins, cell surface receptors, adhesion molecules, and other structural extra-cellular matrix proteins.23They are responsible for the degradation of most extracellular matrix proteins during organogenesis, growth and normal tissue turnover. The expression and activity of MMPs in adult tissues is normally low, but increases significantly in various pathological conditions that may lead to unwanted tissue destruction, such as stroke, inflammatory diseases, tumour growth and metastasis.2-8

[0005] During stroke, MMPs are expressed in various cell types including circulating neutrophils, neurones, astrocytes, microglia, endothelial cells, and infiltrating inflammatory cells.3-8

[0006] Blood brain barrier (BBB) disruption is an important component of stroke pathogenesis. There is robust induction of MMPs at the BBB which facilitate extracellular matrix degradationleading to BBB leakage, leukocyte infiltration, brain oedema, and haemorrhage. MMP-9 and to a lesser extent MMP-2 have traditionally been considered the central mediators of ischaemic BBB disruption because of their ability to degrade components of microvascular basal lamina, especially collagen type-IV, and to disrupt tight junction proteins.2-12Recent data suggest that MMP-12 activity may also be an important mediator of ischaemic injury.7

[0007] A significant amount of interest has focused on MMP-9 (gelatinase B, 92 kDa type IV collagenase) which is produced in a latent form in cells including circulating neutrophils, endothelial cells, astrocytes and neurones and after release to the extracellular space, is activated by cleavage of the pro-peptide.34It is involved in the breakdown of the extracellular matrix in various physiological processes, such as embryonic development, reproduction, angiogenesis, bone development, wound healing, cell migration, and learning and memory.34

[0008] On the other hand, enhanced expression and activity of MMP-9 have been observed during numerous diseases such as epilepsy, bipolar disorders, schizophrenia, Alzheimer’s disease, multiple sclerosis, brain tumours, Guillain-Barre syndrome and stroke.2-4

[0009] During stroke, there is enhanced expression and activity of MMP-9.2-4’8 9Strategies that have targeted MMP-9 inhibition in experimental stroke show marked efficacy in reducing infarction volume and improving functional outcome. These approaches include gene silencing that inhibit MMP-9 using MMP-9 siRNA (delivered using viral vectors), MMP-9 neutralizing monoclonal antibodies and re-purposed drugs such as minocycline and carnosine.2-8However, MMP inhibition has not so far been tested in large human stroke trials.

[0010] Recent studies also suggest that MMP-12 may have similar deleterious effects during ischaemia. MMP-12 targets a broad spectrum of extracellular matrix proteins including elastin, collagen type IV, and fibronectin. Interestingly, as well as direct effects of its own, MMP-12 has the ability to activate other MMPs such as MMP-2 and MMP-3 which can synergistically contribute to the proteolytic cascade by activating Pro-MMP-9 and in turn activate MMP-9.6’7’10MMP-12 activation also induces myelin basic protein (MBP) degradation and other substrates include pro-TNFa, plasminogen and fibrinogen.11 12

[0011] The compound of Formula (I) (also known as “AZD1236") is disclosed as Example 1 in WO 2006 / 004532 for the treatment of obstructive airway diseases and is a potent inhibitor of both MMP-9 and MMP-12. The compound has a unique overall selectivity profile and no hepatic enzyme induction. AZD1236 inhibits MMPs by direct binding to the catalytic sites of the enzymes. In pre-clinical studies, AZD1236 reversibly inhibited isolated human MMP-9 and MMP-12 enzymatic activity with IC50 of 4.5 nM and 6.1 nM, respectively. The compound exhibits 10- to 15-fold selectivity to MMP-2 and MMP-13 and >350-fold selectivity to othermembers of the enzyme family.13AZD1236 was initially developed for use in chronic obstructive pulmonary disease (COPD)14 15.

[0012] As described herein, the inventors have found AZD1236 improves infarct volume and long-term functional outcomes in in-vivo stroke models. AZD1236 also advantageously treats post-stroke pain.BRIEF SUMMARY OF THE DISCLOSURE

[0013] In accordance with the present invention, there is provided a compound of Formula (I), or a pharmaceutical salt thereof:for use in the treatment of stroke in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

[0014] It may be that the stroke is ischaemic stroke, for example, acute ischaemic stroke. It may be that the stroke is haemorrhagic stroke.

[0015] It may be that the compound is administered to the subject less than 4 hours from stroke onset. It may be that the compound is administered to the subject less than 2 hours from stroke onset. For example, it may be that the compound is administered to the subject less than 1 hour from stroke onset.

[0016] Also provided, is a compound of Formula (I), or a pharmaceutical salt thereof:for use in the treatment of post-stroke pain in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

[0017] It may be that the compound is administered to the subject less than 4 hours from stroke onset. It may be that the compound is administered to the subject less than 2 hoursfrom stroke onset. For example, it may be that the compound is administered to the subject less than 1 hour from stroke onset.

[0018] Also provided, is a compound of Formula (I), or a pharmaceutical salt thereof:for use in preventing or reducing the risk of iatrogenic stroke in a subject.

[0019] It may be that the compound is administered preoperatively. It may be that the compound is administered intraoperatively. It may be that the compound is administered postoperatively.

[0020] Also provided, is a method of treating stroke in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, wherein the compound is administered to the subject less than 6 hours from stroke onset, thereby treating the stroke.

[0021] Also provided, is the use of a compound of Formula (I), or a pharmaceutical salt thereof, for the manufacture of a medicament for the treatment of stroke in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

[0022] Also provided, is a method of treating post-stroke pain in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, wherein the compound is administered to the subject less than 6 hours from stroke onset, thereby treating the post-stroke pain.

[0023] Also provided, is the use of a compound of Formula (I), or a pharmaceutical salt thereof, for the manufacture of a medicament for the treatment of post-stroke pain in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

[0024] Also provided, is a method of preventing or reducing the risk of iatrogenic stroke in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutical salt thereof, thereby preventing or reducing the risk of iatrogenic stroke.

[0025] Also provided, is the use of a compound of Formula (I), or a pharmaceutical salt thereof, for the manufacture of a medicament for preventing or reducing the risk of iatrogenic stroke in a subject.

[0026] Also provided, is a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutical salt thereof, and a pharmaceutically acceptable excipient. In some embodiments the pharmaceutical composition is a parenteral pharmaceutical composition. In some embodiments the pharmaceutical composition is an intravenous pharmaceutical composition. In some embodiments the pharmaceutical composition is an oral pharmaceutical composition, for example an oral tablet, granule or capsule.

[0027] Further aspects and features of the invention are set out in the detailed description below.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In Figures 1 to 27 described below, the compound of the invention (“AZD1236” or “AZD”) was dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water. The corresponding vehicle used (“vehicle” or “Veh”) was 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water.

[0029] Figure 1 - shows the infarct volume in young male mice, 48 hours post permanent middle cerebral artery occlusion (pMCAO). 200 mg / kg of AZD1236 (“AZD”) was administered to the mice at 2, 4, or 6 hours post ischaemia onset, and a further 200 mg / kg of AZD1236 was administered to the mice at 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV (intravenous) bolus immediately followed by 100 mg / kg p.o (per os (oral administration by gavage)). The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0030] Figure 2 - shows the functional outcome in young male mice 0, 7, 14, 21 , and 28 days post pMCAO. Fig. 2A) 200 mg / kg of AZD1236 was administered 2 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. Fig. 2B) 200 mg / kg of AZD1236 was administered 4 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. Fig. 2C) 200 mg / kg of AZD1236 was administered 6 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0031] Figure 3 - shows the blood-brain barrier (BBB) breakdown in young male mice following pMCAO. ‘Sham’ group: mice underwent the same surgical procedure as the pMCAO group, but they did not have the occlusion of the middle cerebral artery. ‘pMCAO’ group: mice with permanent occlusion of the MCA but no further treatment. ‘Vehicle’ group: mice with pMCAO - 200 pL of the vehicle was administered at 2 hours post pMCAO (100 pL of the vehicle was administered via IV bolus immediately followed by 100 pL of the vehicle via p.o.), followed by 200 pL of the vehicle administered by p.o. at 24 hours post pMCAO. ‘AZD’ group:mice with pMCAO - 200 mg / kg of AZD1236 was administered at 2 hours and at 24 hours post onset of pMCAO. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0032] Figure 4 - shows the infarct volume in young female mice, 48 hours post pMCAO. 200 mg / kg of AZD1236 (“AZD”) was administered at 2 hours and at 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0033] Figure 5 - shows the functional outcome in young female mice 0, 7, 14, 21 , and 28 days post pMCAO. Fig. 5A) 200 mg / kg of AZD1236 was administered at 2 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. Fig. 5B) 200 mg / kg of AZD1236 was administered at 4 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. Fig. 2C) 200 mg / kg of AZD1236 was administered at 6 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0034] Figure 6 - shows the infarct volume in aged male mice, 48 hours post pMCAO. 200 mg / kg of AZD1236 (“AZD”) was administered at 2 hours and at 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0035] Figure 7 - shows the functional outcome in aged male mice 0, 7, 14, 21 , and 28 days post pMCAO. 200 mg / kg of AZD1236 was administered at 2 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0036] Figure 8 - shows the infarct volume in aged female mice, 48 hours post pMCAO. 200 mg / kg of AZD1236 (“AZD”) was administered at 2 hours and 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0037] Figure 9 - shows the functional outcome in aged female mice, 0, 7, 14, 21 , and 28 days post pMCAO. 200 mg / kg of AZD1236 was administered at 2 hours post ischaemia onset,followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0038] Figure 10 - shows the infarct volume in young male mice, 48 hours post transient middle cerebral artery occlusion (tMCAO). 200 mg / kg of AZD1236 (“AZD”) was administered at 2, 4, or 6 hours and at 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0039] Figure 11 - shows the functional outcome in young male mice 0, 7, 14, 21 , and 28 days post tMCAO. Fig. 11A) 200 mg / kg of AZD1236 was administered at 4 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. Fig.11 B) 200 mg / kg of AZD1236 was administered at 6 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 4 hours or 6 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0040] Figure 12 - shows the blood-brain barrier (BBB) breakdown in young male mice following tMCAO. ‘Sham’ group: mice underwent the same surgical procedure as the tMCAO group, but they did not have the occlusion of the middle cerebral artery. ‘tMCAO’ group: mice with transient occlusion of the MCA but no further treatment. ‘Vehicle’ group: mice with tMCAO 200 pL of the vehicle was administered at 2 hours post tMCAO (100 pL of the vehicle was administered via IV bolus immediately followed by 100 pL of the vehicle administered via p.o.) followed by 200 pL of the vehicle administered by p.o. at 24 hours post tMCAO. ‘AZD’ group: mice with tMCAO - 200 mg / kg of AZD1236 was administered at 2 hours and at 24 hours post onset of tMCAO. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0041] Figure 13 - shows the infarct volume in young female mice, 48 hours post tMCAO. 200 mg / kg of AZD1236 was administered at 2 or 4 hours post ischaemia onset, followed by administration at 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2 or 4 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0042] Figure 14 - shows the functional outcome in young female mice, 0, 7, 14, 21 , and 28 days post tMCAO. Fig. 14A) 200 mg / kg of AZD1236 was administered at 2 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days.Fig.14B) 200 mg / kg of AZD1236 was administered at 4 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2, or 4 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0043] Figure 15 - shows the infarct volume in aged male mice, 48 hours post tMCAO. 200 mg / kg of AZD1236 was administered 2 hours and 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0044] Figure 16 - shows the functional outcome in aged male mice, 0, 7, 14, 21 , and 28 days post tMCAO. 200 mg / kg of AZD1236 was administered at 2 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0045] Figure 17 - shows the infarct volume in aged female mice, 48 hours post tMCAO. 200 mg / kg of AZD1236 was administered 2 hours and 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0046] Figure 18 - shows the functional outcome in aged female mice, 0, 7, 14, 21 , and 28 days post tMCAO. 200 mg / kg of AZD1236 was administered at 2 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0047] Figure 19 - shows the efficacy of AZD1236 in obese male mice with pMCAO. Fig. 19A) shows the infarct volume in obese male mice, 48 hours post pMCAO. 200 mg / kg of AZD1236 was administered 2 hours and 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o. Fig. 19B) shows the functional outcome in obese male mice 0, 7, 14, 21 , and 28 days post pMCAO. 200 mg / kg of AZD1236 was administered at 2 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0048] Figure 20 - shows the efficacy of AZD1236 in obese male mice with tMCAO. Fig. 20A) shows the infarct volume in obese male mice, 48 hours post tMCAO. 200 mg / kg of AZD1236 was administered 2 hours and 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o. Fig. 20B) shows the functional outcome in obese male mice 0, 7, 14, 21 , and 28 days post tMCAO. 200 mg / kg of AZD1236 was administered at 2 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0049] Figure 21 - shows the BBB integrity in young male mice, 24 hours post tMCAO. 200 mg / kg of AZD1236 was administered to the mice at 2 hours tMCAO. The 200 mg / kg dose of AZD1236 was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. Relaxation times T 1 (longitudinal, Fig. 21 B) and T2 (transversal, Fig. 21 A) maps were acquired (RARE-VTR) pre and post gadolinium contrast administration (GBCA) and the ratio of numerical distribution of T1 and T2 values were analysed as a result of gadolinium injections. Values of <1 for pre vs post gadolinium treatment indicate a greater perfusion of the contrast agent in vehicle (“vhl”) treated mice than the AZD 1236 (“AZD”) treated mice, suggesting a better integrity of the blood brain barrier in the AZD1236 treated mice.

[0050] Figure 22 - these experiments were performed on male mice with tMCAO. Fig. 22A) Shows the AZD1236 concentration (nM) in the brain over time (after AZD1236 administration). At 2 hours post ischemia onset, AZD1236200 mg / kg was administered to young male and old male mice, and AZD1236 100 mg / kg IV bolus was administered to obese male mice. Fig. 22B) Shows the AZD1236 concentration (nM) in plasma over time (after AZD1236 administration). AZD1236 200 mg / kg was administered to young male and old male mice, and AZD1236 100 mg / kg was administered to obese male mice at 2 hours post ischaemia onset. The 200 mg / kg dose of AZD1236 in young and old male mice was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0051] Figure 23 - these experiments were performed on female mice with tMCAO. Fig. 23A) Shows the AZD1236 concentration (nM) in the brain over time (after AZD1236 administration). AZD1236 200 mg / kg was administered to young female and old female mice at 2 hours post ischaemia onset. Fig. 23B) Shows the AZD1236 concentration (nM) in plasma over time (after AZD1236 administration). AZD1236 200 mg / kg was administered to young female and old female mice at 2 hours post ischaemia onset. The 200 mg / kg dose of AZD1236 was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0052] Figure 24 - Shows the withdrawal response in young male mice to 2 g von Frey filament over time, post pMCAO. 200 mg / kg of AZD1236 was administered at 2 hours (Fig. 24A), 4 hours (Fig. 24B), or 6 hours (Fig. 24C) post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0053] Figure 25 - Shows the withdrawal latency in young male mice over time, post pMCAO. 200 mg / kg of AZD1236 was administered at 2 hours (Fig. 25A), 4 hours (Fig. 25B), or 6 hours (Fig. 25C) post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0054] Figure 26 - Shows the withdrawal response in young female mice to 2 g von Frey filament over time, post pMCAO. 200 mg / kg of AZD1236 was administered at 2 hours (Fig. 26A), 4 hours (Fig. 26B), or 6 hours (Fig. 26C) post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0055] Figure 27 - pMCAO (young male mice), thermal hyperalgesia. Shows the withdrawal latency in young male mice overtime, post pMCAO. 200 mg / kg of AZD1236 was administered at 2 hours (Fig. 27A), 4 hours (Fig. 27B), and 6 hours (Fig. 27C) post ischaemia onset, followed by 200 mg / kg of AZD1236 administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0056] Figure 28 - shows the haemorrhage volume in young male mice, 24 hours post ICH. 200 mg / kg of AZD1236 was administered to the mice at 2, 4, or 6 hours post haemorrhage onset. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV (intravenous) bolus immediately followed by 100 mg / kg p.o. The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.DETAILED DESCRIPTION

[0057] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, thespecification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0058] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0059] For the avoidance of doubt, the information disclosed earlier in this specification under the heading “Background” is relevant to the invention and is to be read as part of the disclosure of the invention.

[0060] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.Definitions

[0061] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0062] Reference to “stroke” refers to a medical condition in which blood flow to the brain is blocked or there is sudden bleeding in the brain, which causes cell death. There are two main types of stroke: ischaemic stroke and haemorrhagic stroke. An “ischaemic stroke” occurs when there is a blockage in a blood vessel, resulting in a restricted blood supply to the brain. A “haemorrhagic stroke” occurs when a blood vessel ruptures, causing blood to leak into the intracranial cavity.

[0063] An “iatrogenic stroke” is a stroke that can occur intraoperatively, or within 30 days of a surgical procedure, and can be categorised as either overt or covert, occurring without obvious acute neurological symptoms.

[0064] A “wake-up stroke” is a stroke with an unknown exact time of stroke onset, as the stroke is noted on awakening by the subject. Thus, a wake-up stroke occurs whilst the subjectis sleeping, and as such the subject wakes up with the symptoms of a stroke. Accordingly, the subject first becomes symptomatic on awakening. Prior to sleeping, the subject was last known to be healthy and did not experience any stroke symptoms.

[0065] Reference to “stroke onset”, or any reference to an onset of stroke such as post ischaemia onset, refers to the time from which the subject first becomes symptomatic, i.e. the time from which any stroke symptom appears (t = 0). Prior to stroke onset, the subject was last known to be healthy and did not experience any stroke symptoms. The main symptoms of stroke are categorised by the FAST test (Face, Arms, Speech, and Time (FAST)):Face - the face of the subject may have dropped on one side, the subject may not be able to smile, or their mouth or eye may have drooped.Arms - the subject may not be able to lift both arms and keep them lifted due to weakness or numbness in one arm.Speech - the subject’s speech may be slurred or garbled, or the subject may not be able to talk despite appearing to be awake. The subject may also have problems understanding speech.Time - if any of the above signs or symptoms are recognised, it is time to call the emergency services.

[0066] Other symptoms of stroke include, but are not limited to: sudden numbness or weakness in the face, arm, or leg (especially on one side of the body), complete paralysis of one side of the body, sudden loss or blurring of vision (in one or both eyes), being or feeling sick, dizziness, confusion, difficulty understanding speech, loss of balance, lack of coordination, trouble walking, difficulty swallowing (dysphagia), a sudden and very severe headache with no known cause, and loss of consciousness.

[0067] Reference to “post-stroke pain” (also known as central pain, or thalamic pain) refers to a condition whereby a subject who has experienced a stroke subsequently develops severe pain. It may be that post-stroke pain arises immediately after the stroke. It may be that poststroke pain arises 1 day to 7 days after the stroke. It may be that post-stroke pain arises 7 days to 14 days after the stroke. It may be that post-stroke pain arises up to 1 month after the stroke. It may be that post-stroke pain arises up to 6 months after the stroke. It may be that post-stroke pain arises up to 1 year after the stroke. It may be that post-stroke pain arises 1 year or later after the stroke. Post-stroke pain may include the following symptoms, but not limited to: burning, aching and prickling. Post-stroke pain may affect different body parts of the subject, including, but not limited to: the face, arm, leg, trunk, or the entire half of the body.

[0068] The term “a compound of the invention”, or the like refers to a compound of Formula (I), or a pharmaceutical salt thereof.

[0069] Reference to a “composition of the invention” refers to a pharmaceutical composition comprising a compound of the invention (e.g. a compound of Formula (I)), or a pharmaceutical salt thereof, and a pharmaceutically acceptable excipient. For example, any of the pharmaceutically acceptable excipients described herein.

[0070] For the avoidance of doubt, the compound of Formula (I) as defined herein, is also known as ‘AZD1236’. Thus, any reference to AZD1236 herein, also refers to the compound of Formula (I). As such, these terms can be used interchangeably throughout the specification. Accordingly, AZD1236 has the following compound structure:Formula (I) (AZD1236)

[0071] The preparation of AZD1236 is described in WO 2006 / 004532 (see, for example, Example 1 , page 20). The full chemical name for AZD1236 is (5S)-5-({[4-(2- cyclopropylprimidin-5-yl)ethynyl]-3,6-dihydropyridin-1 (2H)-yl]sulfonyl}methyl]-5- methylimidazolidine-2, 4-dione.

[0072] The invention contemplates pharmaceutically acceptable salts of the compound of the invention. These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds.

[0073] The terms “pharmaceutical salt” or “pharmaceutically acceptable salt” refer to salts that retain the biological effectiveness and properties of the compounds described herein and, which are not biologically or otherwise undesirable. A suitable pharmaceutically-acceptable salt of a compound is, for example, an acid-addition salt of a compound, for example an acidaddition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. It may be that the pharmaceutically acceptable salt is a salt with an organic base, preferably an organic amine. For example, it may be that the pharmaceutically acceptable salt is methylamine, dimethylamine, trimethylamine, or tris-(2-hydroxyethyl)amine. Hemisalts of acids and bases may also be formed, for example a hemicalcium salt. For a review on suitablepharmaceutically acceptable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0074] In some embodiments the compound of the invention is in the free base form.

[0075] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S- sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. Where a compound of the invention has two or more stereocentres any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example racemic mixtures and other enantiomeric mixtures, and diastereomeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer the compounds may still contain other diastereoisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85%.

[0076] The compounds of this invention possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- andZ- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof.

[0077] Compounds and salts described in this specification may be isotopically-labelled (or “radio-labelled”). Accordingly, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include2H (also written as “D” for deuterium),3H (also written as “T” for tritium),11C,13C,14C,15O,17O,18O,18F and the like. The radionuclide that is used will depend on the specific application of that radio-labelled derivative. For example, for in vitro competition assays,3H or14C are often useful. For radioimaging applications,11C or18F are often useful. In some embodiments, the radionuclide is3H. In some embodiments, the radionuclide is14C. In some embodiments, the radionuclide is11C. And in some embodiments, the radionuclide is18F.

[0078] It is also to be understood that certain compounds of the invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms.

[0079] It is also to be understood that certain compounds of the invention may exhibit polymorphism.

[0080] Compounds of the invention may exist in a number of different tautomeric forms and references to compounds of the invention include all such forms.

[0081] The compound of Formula (I) is a MMP-9 and MMP-12 inhibitor. Thus, the compound of Formula (I) has both MMP-9 and MMP-12 inhibitory activity. It may be that the compound of Formula (I) also has MMP-2 inhibitory activity. It may be that the compound of Formula (I) also has MMP-13 inhibitory activity. Thus, the compound of Formula (I) may be a MMP-9, MMP-12, MMP-2 and / or MMP-13 inhibitor.

[0082] The terms “treating” or “treatment”, and the therapies encompassed by this invention, include the following and combinations thereof: (1) reducing the risk of or inhibiting, e.g. delaying, initiation and / or progression of, a state, disorder or condition; (2) preventing, e.g. reducing the risk of, or delaying the appearance of clinical symptoms of a state, disorder or condition developing in a subject (e.g. human or animal) that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (3) inhibiting the state, disorder or condition (e.g., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (4) relieving the condition (e.g. causing regression of the state, disorder orcondition or at least one of its clinical or subclinical symptoms). Where the composition of the invention is used in the treatment of a subject, treatment contemplates any one or more of: maintaining the health of the subject; restoring or improving the health of the subject; and delaying the progression of the disorder. The benefit to a subject to be treated may be either statistically significant or at least perceptible to the subject or to the physician. It will be understood that a medicament will not necessarily produce a clinical effect in every subject to whom it is administered, and this paragraph is to be understood accordingly. The compositions and methods described herein are of use for therapy and / or prophylaxis of stroke and post-stroke pain. The compositions and methods described herein are of use for inhibiting or preventing stroke and post-stroke pain progression.

[0083] As used herein, the terms “prevent” or “preventing” mean decreasing the risk of stroke (e.g. iatrogenic stroke) in a subject. To determine whether the prevention is effective, a comparison can be made between a subject who received a compound of the invention with a subject at risk of a stroke (e.g. iatrogenic stroke) who did not receive the compound of the invention. A comparison can also be made between the subject who received the composition and a control, a baseline, or a known level or measurement.

[0084] The treatments may include maintenance therapy of subjects who have suffered a stroke and whose condition has subsequently improved, e.g. because of treatment. Such subjects may or may not suffer a side-effect of stroke, such as, but not limited to, impaired speech, restricted physical abilities, weakness or paralysis of limbs, difficulty gripping or holding objects, memory loss, pain, fatigue, and a slowed ability to communicate. Maintenance therapy aims to arrest, reduce or delay (re-)occurrence or progression of a stroke. In embodiments, the compound of the invention is administered to the subject over a period of at least 7 days following a stroke. It may be that the compound is administered daily over a period of 7 days following a stroke. It may be that the compound of the invention is administered to the subject over a period of 14 days following a stroke. It may be that the compound of the invention is administered to the subject over a period of 28 days following a stroke. It may be that the compound of the invention is administered to the subject over a period of up to 3 months following a stroke. It may be that the compound of the invention is administered to the subject over a period of up to 6 months following a stroke.

[0085] Reference herein to a “therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of a stroke; reverse, completely stop, or slow the progress of a stroke; or reduce the risk of a stroke getting worse. It is further within the skill of one of ordinary skill in the art to determine appropriate treatment duration, appropriate doses, and any potential combination treatments, based upon an evaluation of therapeutic or prophylactic response.

[0086] The terms "subject" or “patient” refer to a human or non-human animal to whom a compound of the invention is administered. In some embodiments, the subject may be a mammal. In some embodiments, the subject may be a non-mammalian animal. In preferred embodiments, the subject is a human. In some embodiments, the subject is a human that is at least 40, 50, 60, 70, 80, or 90 years old.

[0087] For the avoidance of doubt, ‘thrombectomy’, is also known as ‘mechanical thrombectomy’. Thus, any reference to thrombectomy herein, also refers to mechanical thrombectomy. As such, these terms can be used interchangeably throughout the specification.

[0088] Ingredients and excipients of the described compositions are suitable for the intended purpose. For example, pharmaceutical compositions comprise pharmaceutically acceptable ingredients.

[0089] If not otherwise stated, ingredients, components, excipients etc. of the compositions of the invention are suitable for one or more of the intended purposes discussed elsewhere herein.

[0090] Reference to “about” in the context of a numerical is intended to encompass the value + / - 10%. For example, about 20% includes the range of from 18% to 22%.Therapeutic Uses and Applications

[0091] Herein it is shown that inhibiting both matrix metalloproteinases MMP-9 and MMP-12 is useful in the treatment of stroke or post-stroke pain, or in preventing or reducing the risk of iatrogenic stroke. This can be achieved by administering a compound of Formula (I), which has both MMP-9 and MMP-12 inhibitory activity.Stroke

[0092] Provided herein is a compound of Formula (I), or a pharmaceutical salt thereof:for use in the treatment of stroke in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset. In embodiments, the compound is administered to the subject less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, or less than 1 hour from stroke onset. It may be that the compound is administered 4 hours orless from stroke onset. It may be that the compound is administered 2 hours or less from stroke onset.

[0093] In embodiments, the compound is administered to the subject at stroke onset. It may be that the compound is administered to the subject within about 1 minute to about 30 minutes from stroke onset. It may be that the compound is administered to the subject within about 30 minutes to about 60 minutes from stroke onset. It may be that the compound is administered within about 60 minutes to about 90 minutes from stroke onset. It may be that the compound is administered within about 60 minutes to about 120 minutes from stroke onset. It may be that the compound is administered within about 90 minutes to about 120 minutes from stroke onset. It may be that the compound is administered to the subject within about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 minutes from stroke onset.

[0094] Currently, a subject that has had a stroke has to be pre-diagnosed in a hospital setting before stroke treatment is administered to said subject. The pre-diagnosis step is critical to determine whether the subject has experienced an ischaemic stroke or a haemorrhagic stroke. For example, t-PA cannot be administered to a subject that has experienced a haemorrhagic stroke.

[0095] Advantageously, the compound of the invention can be administered to a subject that has experienced an ischaemic stroke or a haemorrhagic stroke. Thus, a pre-diagnosis step is not required when administering the compound of the invention to a subject. Accordingly, in embodiments, the compound of the invention can be administered to the subject before the subject arrives at the hospital. Thus, it may be that the compound is administered by emergency medical services (EMS) (e.g. paramedics) at the subject’s home. It may be that the compound is administered by emergency medical services (EMS) (e.g. paramedics) in the ambulance.

[0096] In embodiments, the stroke is ischaemic stroke, for example, acute ischaemic stroke. Thus, it may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in the treatment of acute ischaemic stroke in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

[0097] In embodiments, the stroke is haemorrhagic stroke. Thus, it may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in the treatment of haemorrhagic stroke in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

[0098] A stroke may negatively affect a subject’s neurological cognition. For example, after a stroke, a subject may experience cognitive problems with: concentration, memory, executivefunction, spatial neglect, apraxia, visual perception, anosognosia, and agnosia. Thus, in embodiments, it may be that the treatment reduces post-stroke neurological deficit. Accordingly, a subject treated with a composition of the invention (e.g. a compound of Formula (I)), will have reduced post-stroke neurological deficit.

[0099] In embodiments, the stroke is wake-up stroke. Thus, it may be that the compound is administered to the subject less than 6 hours from awakening. It may be that the compound is administered to the subject less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, or less than 1 hour from awakening. It may be that the compound is administered 4 hours or less from awakening. It may be that the compound is administered 2 hours or less from awakening.

[0100] Infarct is an area of necrosis (tissue death) due to the blood vessel blockage caused by an ischaemic stroke. In embodiments, the compound of the invention reduces infarct volume. It may be that the compound of the invention reduces infarct volume by less than about 15%. It may be that the compound of the invention reduces infarct volume by less than about 10%. It may be that the compound of the invention reduces infarct volume by less than about 5%.

[0101] The blood-brain barrier (BBB) can be disrupted by ischaemic and haemorrhagic stroke, which can lead to influx of water molecules and blood components into the brain extracellular space resulting in serious clinical consequences such as vasogenic brain edema and haemorrhagic transformation. Suitably, the compound of the invention reduces BBB damage following stroke onset. It may be that the compound of the invention prevents BBB damage following stroke onset. It may be that the compound of the invention reduces BBB breakdown following stroke onset. It may be that the compound of the invention prevents BBB breakdown following stroke onset.Ischaemic stroke

[0102] Ischaemic strokes are caused by blockage of an artery (or, in rare instances, a vein). Approximately 87% of all strokes are ischaemic strokes.

[0103] An ischaemic stroke occurs when a blood vessel that supplies the brain becomes blocked or "clogged" and impairs blood flow to part of the brain. The brain cells and tissues begin to die within minutes from lack of oxygen and nutrients. Ischaemic strokes can further be divided into the following 3 groups:1) Thrombotic strokes: These are caused by a blood clot that develops in the blood vessels inside the brain.2) Embolic strokes: These are caused by a blood clot or plaque debris that develops elsewhere in the body and then travels to one of the blood vessels in the brain through the bloodstream.3) Lacunar strokes: These are caused by blockage of small blood vessels.

[0104] Thrombotic stroke is usually seen in older subjects, especially those with high cholesterol and atherosclerosis (a buildup of fat and lipids inside the walls of blood vessels) or diabetes. Sometimes, symptoms of a thrombotic stroke can occur suddenly and often during sleep or in the early morning. At other times, it may occur gradually over a period of hours or even days.

[0105] Another type of stroke that occurs in the small blood vessels in the brain is called a lacunar infarct. Lacunar infarctions are often found in people who have diabetes or high blood pressure.

[0106] Embolic strokes often result from heart disease or heart surgery and occur rapidly and without any warning signs. About 15% of embolic strokes occur in people with atrial fibrillation, a type of abnormal heart rhythm in which the upper chambers of the heart do not beat effectively.

[0107] Thus, in embodiments, the stroke is ischaemic stroke. Therefore, it may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in the treatment of ischaemic stroke in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

[0108] In embodiments, the stroke is acute ischaemic stroke. Thus, it may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in the treatment of acute ischaemic stroke in a subject. It may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in the treatment of acute ischaemic stroke in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

[0109] In embodiments, the stroke is a thrombotic stroke. It may be that the stroke is an embolic stroke. It may be that the stroke is an ischaemic stroke such as lacunar stroke or non-lacunar stroke (e.g. cardioembolic, cryptogenic, or large artery).

[0110] Thrombotic strokes may be preceded by one or more "mini-strokes," also known as transient ischaemic attacks (TIAs). TIAs may last for a few minutes or up to 24 hours, and are often a warning sign that a stroke may occur. Although usually mild and transient, the symptoms caused by a TIA are similar to those caused by a stroke (as described herein). Thus, in embodiments, the stroke is a TIA. It may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in the treatment of a TIA in a subject, whereinthe compound is administered to the subject less than 6 hours from TIA onset. Accordingly, if the compound is administered after the subject has experienced a TIA, but before stroke onset, then it may be that the compound of the invention is used in the prevention or reduction of cerebral injury caused by the stroke in a subject, such as a thrombotic stroke.

[0111] In embodiments, the compound of the invention is for use in preventing or reducing the risk of a stroke in a subject, such as a thrombotic stroke. It may be that the subject is at high risk of a stroke. For example, it may be that the subject has experienced a TIA. Thus, it may be that the compound is administered to a subject in the first 30 days after said subject has experienced a TIA.

[0112] Cerebral edema is a serious complication arising from ischaemic stroke. Cerebral edema causes an increase in intracranial pressure, rapid deterioration of neurological symptoms, and formation of cerebral hernia, and is an important risk factor for adverse outcomes after stroke. Haemorrhagic transformation (HT) is also a common complication in patients with acute ischaemic stroke. HT occurs when peripheral blood extravasates across a disrupted blood brain barrier (BBB) into the brain following ischaemic stroke. Neuroinflammation is also a major pathological event involved in the process of ischaemic injury and repair. Acute neuroinflammation occurs immediately upon brain ischaemic injury, lasting a few days. Cytokines and chemokines promote the migration of neutrophils and macrophages to the site of inflammation. Neuroinflammation lasting 2 to 6 weeks is designated subacute neuroinflammation, while chronic neuroinflammation lasts for months or years. Macrophages, lymphocytes, and plasma cells predominate in chronic neuroinflammation, in contrast to the neutrophils that predominate in acute neuroinflammation. Late post-ischaemic neuroinflammation leads to secondary damage of neuronal cells. Once the cascade of events is initiated, the process of neuroinflammation can become overactivated, resulting in further cellular damage and loss of neuronal functions.

[0113] Thus, in embodiments, the treatment prevents or inhibits one or more of brain edema, haemorrhagic transformation, and neuroinflammation. Accordingly, a composition of the invention will also prevent or inhibit one or more of brain edema, haemorrhagic transformation, and neuroinflammation. It may be that the treatment prevents or inhibits brain edema. It may be that the treatment prevents or inhibits haemorrhagic transformation. It may be that the treatment prevents or inhibits neuroinflammation. It may be that the treatment prevents or inhibits brain edema and haemorrhagic transformation. It may be that the treatment prevents or inhibits brain edema, haemorrhagic transformation, and neuroinflammation.Haemorrhagic stroke

[0114] Haemorrhagic strokes occur when a blood vessel that supplies the brain ruptures and bleeds. When an artery bleeds into the brain, brain cells and tissues do not get oxygen and nutrients. In addition, pressure builds up in surrounding tissues and irritation and swelling can occur, which can lead to further brain damage. Haemorrhagic strokes are divided into the following 2 main categories:• Intracerebral haemorrhage: wherein bleeding is from the blood vessels within the brain.• Subarachnoid haemorrhage: wherein bleeding is in the subarachnoid space (the space between the brain and the membranes that cover the brain (i.e. meninges)).

[0115] Intracerebral haemorrhage is usually caused by high blood pressure.

[0116] Subarachnoid haemorrhage is often caused by an aneurysm or an arteriovenous malformation (AVM). It can also be caused by trauma.

[0117] Thus, in embodiments, the stroke is a haemorrhagic stroke. Therefore, it may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in the treatment of haemorrhagic stroke in a subject. It may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in the treatment of haemorrhagic stroke in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

[0118] In embodiments, it may be that the stroke is an intracerebral haemorrhagic stroke. It may be that the stroke is a subarachnoid haemorrhagic stroke.Post-Stroke Pain

[0119] A subject who has experienced a stroke may subsequently develop severe pain, also known as post-stroke pain. Post-stroke pain may include the following symptoms, but not limited to: burning, aching and prickling. Post-stroke pain may affect different body parts of the subject, including, but not limited to: the face, arm, leg, trunk, or the entire half of the body.

[0120] Thus, provided herein is a compound of Formula (I), or a pharmaceutical salt thereof:for use in the treatment of post-stroke pain in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset. In embodiments, the compound is administered to the subject less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, or less than 1 hour from stroke onset. It may be that the compound is administered 4 hours or less from stroke onset. It may be that the compound is administered 2 hours or less from stroke onset.

[0121] In embodiments, the compound is administered to the subject at stroke onset. It may be that the compound is administered to the subject within about 1 minute to about 30 minutes from stroke onset. It may be that the compound is administered to the subject within about 30 minutes to about 60 minutes from stroke onset. It may be that the compound is administered within about 60 minutes to about 90 minutes from stroke onset. It may be that the compound is administered within about 60 minutes to about 120 minutes from stroke onset. It may be that the compound is administered within about 90 minutes to about 120 minutes from stroke onset. It may be that the compound is administered to the subject within about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 minutes from stroke onset.

[0122] As discussed above, the compound of the invention can advantageously be administered to a subject that has experienced an ischaemic stroke or a haemorrhagic stroke. Thus, a pre-diagnosis step is not required when administering the compound of the invention to a subject. Accordingly, in embodiments, the compound of the invention is administered to the subject before the subject arrives at the hospital. Thus, it may be that the compound is administered by emergency medical services (EMS) (e.g. paramedics) at the subject’s home. It may be that the compound is administered by emergency medical services (EMS) (e.g. paramedics) in the ambulance.

[0123] In embodiments, it may be that post-stroke pain arises immediately after the stroke. It may be that post-stroke pain arises 1 day to 7 days after the stroke. It may be that post-stroke pain arises 7 days to 14 days after the stroke. It may be that post-stroke pain arises up to 1 month after the stroke. It may be that post-stroke pain arises up to 6 months after the stroke. It may be that post-stroke pain arises up to 1 year or longer after the stroke.

[0124] In embodiments, the post-stroke pain includes muscle and joint pain, such as spasticity, hypertonia, contractures, and shoulder pain (e.g. capsulitis, subluxation). It may be that the post-stroke pain includes headaches. It may be that the post-stroke pain includes a swollen hand.

[0125] In embodiments, the post-stroke pain is central post-stroke pain (CPSP). CPSP is also known as neuropathic pain, or central pain syndrome. Thus, it may be that thepost-stroke pain is post-stroke neuropathic pain. Subjects with central post-stroke pain may experience sensations such as tingling, burning, throbbing, shooting pain, pins and needles, and numbness.

[0126] In embodiments, the post-stroke pain is allodynia (e.g. mechanical allodynia) or hyperalgesia (e.g. thermal hyperalgesia). Thus, it may be that the post-stroke pain is allodynia (e.g. mechanical allodynia). It may be that the post-stroke pain is hyperalgesia (e.g. thermal hyperalgesia). Preferably, it may be that the post-stroke pain is mechanical allodynia.

[0127] In embodiments, the compound of the invention prevents development of allodynia. It may be that the compound of the invention prevents development of mechanical allodynia.Iatrogenic Stroke

[0128] Also provided, is a compound of Formula (I), or a pharmaceutical salt thereof:for use in preventing or reducing the risk of iatrogenic stroke in a subject.

[0129] It may be that the iatrogenic stroke is caused by or associated with a surgical procedure. It may be that the surgical procedure is a cardiac surgical procedure. Thus, it may be that the iatrogenic stroke is caused by or associated with a cardiac surgical procedure. It may be that the cardiac surgical procedure is selected from, but not limited to: cardiac valve surgery (such as transcatheter aortic valve replacement (TAVR) or transcatheter aortic valve implantation (TAVI), or coronary artery bypass grafting), coiling or treatment of an aneurysm and an extracranial or intracranial endovascular procedure (e.g. stenting).

[0130] It may be that the compound is administered to the subject prior to the commencement of a surgical procedure (e.g. a cardiac surgical procedure). Thus, it may be that the compound is administered preoperatively.

[0131] It may be that the compound is administered to the subject during a surgical procedure (e.g. a cardiac surgical procedure). Thus, it may be that the compound is administered intraoperatively.

[0132] It may be that the compound is administered to the subject after a surgical procedure (e.g. a cardiac surgical procedure). Thus, it may be that the compound isadministered postoperatively. It may be that the compound is administered to the subject within 30 days of a surgical procedure (e.g. a cardiac surgical procedure). For example, it may be that the compound is administered to the subject 1 day after a surgical procedure, it may be that the compound is administered to the subject for up to 7 days after a surgical procedure, or it may be that the compound is administered to the subject for up to 14 days after a surgical procedure. It may be that the compound is administered to the subject for 1 day to 7 days, 7 days to 14 days, or 14 days to 21 days after a surgical procedure (e.g. a cardiac surgical procedure). Thus, it may be that the compounds is administered to the subject for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after a surgical procedure (e.g. a cardiac surgical procedure).

[0133] It may be that the compound is administered to the subject prior to the commencement of a surgical procedure (e.g. a cardiac surgical procedure), and after the surgical procedure (e.g. a cardiac surgical procedure). Thus, it may be that the compound is administered both preoperatively and postoperatively. For example, it may be that the compound is administered to the subject preoperatively, and also for up to 7 days after the surgical procedure. It may be that the compound is administered to the subject preoperatively, intraoperatively, and / or postoperatively.

[0134] In embodiments, it may be that a compound of the invention, or a pharmaceutical salt thereof, is for use in treating and / or preventing perioperative strokes. It may be that a perioperative stroke is selected from preoperative stroke, intraoperative stroke and postoperative stroke. Thus, it may be that a compound of the invention, or a pharmaceutical salt thereof, is for use in treating and / or preventing preoperative, intraoperative and / or post-operative strokes.

[0135] Accordingly, it may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in treating perioperative strokes. It may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in treating preoperative strokes. It may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in treating intraoperative strokes. It may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in treating postoperative strokes.

[0136] It may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in preventing perioperative strokes. It may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in preventing preoperative strokes. It may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in preventing intraoperative strokes. It may be that the compound of Formula (I), or a pharmaceutical salt thereof, is for use in preventing post-operative strokes.Pharmaceutical Compositions

[0137] Also provided herein is a pharmaceutical composition comprising the compound of the invention, or a pharmaceutical salt thereof, and a pharmaceutically acceptable excipient.

[0138] The pharmaceutical compositions of the invention may be used in any of the methods, uses, or embodiments described herein. For example, it may be that a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutical salt thereof, and a pharmaceutically acceptable excipient, is for use in the treatment of stroke in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset. It may be that a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutical salt thereof, and a pharmaceutically acceptable excipient, is for use in the treatment of post-stroke pain in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset. It may be that a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutical salt thereof, and a pharmaceutically acceptable excipient, is for use in preventing or reducing the risk of iatrogenic stroke in a subject.

[0139] Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988. Pharmaceutical excipients suitable for the preparation of dosage forms are well known, for example as described in the Handbook of Pharmaceutical Excipients, Seventh Edition, Rowe et a! , and in R. D. Pockle et al., “A comprehensive review on pharmaceutical excipients”, Ther Deliv. 2023 Jul;14(7):443-458.

[0140] In embodiments, the compound of the invention is suitably compounded with an appropriate and convenient amount of excipients which may vary from about 1 to about 99 percent by weight of the total composition. In embodiments, the compound of the invention is dissolved in pharmaceutical composition of the invention. In embodiments, the compound of the invention is present in the pharmaceutical composition as a dispersion. The compositions may be prepared using conventional procedures well known in the art.

[0141] In embodiments, the pharmaceutical composition comprises a compound of the invention, or a pharmaceutical salt thereof, a pharmaceutically acceptable excipient, and at least one solvent.

[0142] In embodiments, the compound of the invention is present in the pharmaceutical composition in an amount of up to about 99% by weight of the composition, for example up to 95%, up to 90%, up to 80%, up to 70%, up to 60%, up to 50%, up to 40%, up to 30%, up to 20%, or up to 10% by weight of the composition.

[0143] In embodiments, the compositions may be in a form suitable for parenteral administration. For example, as a sterile aqueous or oily solution for intravenous, intraarterial, subcutaneous, or intramuscular dosing. Preferably, the composition may be in a form suitable for intravenous administration.

[0144] In embodiments, the compositions may be in a form suitable for oral use. For example, as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, sprays or elixirs.

[0145] In embodiments, the pharmaceutical composition described herein further comprises a stabiliser, in order to prevent the degradation of the active compound and to provide a longer shelf life. It may be that the stabiliser is an antioxidant, a chelating compound or a photo- protective compound, or a combination thereof.

[0146] The pharmaceutical compositions of the invention optionally further comprise one or more excipients selected from viscosity modifying agents, emulsifiers, surfactants, humectants, oils, waxes, additional solvents, preservatives, pH modifying agents (for example a suitable acid or base, for example an organic acid or organic amine base), buffers, antioxidants (for example butylated hydroxyanisol, butylated hydroxytoluene or vitamin E), crystallisation inhibitors (for example a cellulose derivative such as hydroxypropyl methyl cellulose), colorants, and fragrances, or combinations thereof. For example, it may be that the pharmaceutical composition further comprises one or more excipients selected from buffers, antioxidants, preservatives, viscosity modifying agents, or surfactants, or combinations thereof. It may be that the pharmaceutical composition further comprises a viscosity modifying agent such as a glycol. It may be that the glycol is a non-polymeric glycol (for example an alkylene glycol, e.g. a C2-8 alkylene glycol such as ethylene glycol or propylene glycol); a polymeric glycol (for example a poly(alkylene glycol), e.g. a polyethylene glycol such as triethylene glycol, or a polypropylene glycol); or a glycol ether (including (poly)alkyleneglycol (poly)alkylethers such as propylene glycol dimethyl ether (proglyde) or diethylene glycol diethyl ether; or 2-(2-ethoxyethoxy)ethanol (Transcutol)). Thus, it may be that the pharmaceutical composition further comprises triethylene glycol. Representative examples of such additional excipients are well known, for example as listed in the Handbook of Pharmaceutical Excipients, 7thEdition, Rowe et al.Routes of Administration

[0147] The compound of the invention may be administered to a subject by any suitable route of administration, appropriate for the condition to be treated and the pharmaceutically active agent to be used.

[0148] Routes of administration include, but are not limited to, oral (e.g., by ingestion, tablets, sprays etc.); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, dressing etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose); nasogastric; rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; or by implant. Preferred routes of administration include intravenous administration, intraarterial administration, oral administration, and nasogastric administration.

[0149] It may be that the compound of the invention is administered to the subject by any of the aforementioned administration routes prior to, during, and / or after a surgical procedure (e.g. a cardiac surgical procedure).

[0150] It may be that the compound of the invention is administered to the subject parenterally. It may be that the compound of the invention is administered to the subject intravenously. Thus, it may be that the compound of the invention is administered to the subject prior to, during, and / or after a surgical procedure (e.g. a cardiac surgical procedure), wherein the compound is administered intravenously. It may be that the compound of the invention is administered to the subject less than 6 hours from stroke onset, wherein the compound is administered intravenously.

[0151] It may be that the compound of the invention is administered to the subject intraarterially. Thus, it may be that the compound of the invention is administered to the subject prior to, during, and / or after a surgical procedure (e.g. a cardiac surgical procedure), wherein the compound is administered intraarterially. It may be that the compound of the invention is administered to the subject less than 6 hours from stroke onset, wherein the compound is administered intraarterially.

[0152] It may be that the compound of the invention is administered to the subject orally. Thus, it may be that the compound of the invention is administered to the subject prior to, during, and / or after a surgical procedure (e.g. a cardiac surgical procedure), wherein the compound is administered orally. It may be that the compound of the invention is administered to the subject less than 6 hours from stroke onset, wherein the compound is administered orally.

[0153] It may be that the compound of the invention is administered to the subject nasogastrically. Thus, it may be that the compound of the invention is administered to thesubject prior to, during, and / or after a surgical procedure (e.g. a cardiac surgical procedure), wherein the compound is administered nasogastrically. It may be that the compound of the invention is administered to the subject less than 6 hours from stroke onset, wherein the compound is administered nasogastrically.

[0154] In embodiments, the compound of the invention is first administered to the subject less than 6 hours from stroke onset, wherein the compound is administered intravenously. It may be that the compound of the invention is then administered to the subject orally, over a period of 7 days following the stroke (e.g., wherein the compound is administered daily).Dosage and Dosage Regimens

[0155] Typically, the dose formulated for a particular pharmaceutically active agent (e.g. a compound of the invention) will be around the equivalent of the normal single dose multiplied by the number times greater the expected duration of action the formulation is to provide. Evidently, this amount will need to be tailored to take into account any adverse effects of a large dose at the beginning of treatment and so this will generally be the maximum dose used. The precise amount suitable in any case will readily be determined by suitable experimentation.

[0156] The duration of treatment will depend upon the nature of the condition or disorder being treated. Suitably, the administration of the compound is continued until the condition is eradicated and / or the symptoms of the condition are reduced or eliminated. The upper limit of the period of treatment can be readily determined by a physician.

[0157] The frequency of administration of the composition of the invention will depend upon a number of factors that may readily be determined by a physician, for example the severity of the condition, the responsiveness to initial treatment and the particular condition being treated. For example, It may be that the subject is administered an initial intravenous dose of the compound, followed by one or more orally administered doses of the compound. It may be that the orally administered doses of the compound are administered once daily. It may be that the orally administered doses of the compound are administered more than once daily. For example, it may be that the orally administered doses of the compound are administered twice daily. It may be that the orally administered doses of the compound are administered over a period of one day. It may be that the orally administered doses of the compound are administered over a period of up to three days. It may be that the orally administered doses of the compound are administered over a period of up to seven days. It may be that the orally administered doses of the compound are administered over a period of up to fourteen days.

[0158] In embodiments, the subject is administered an initial intravenous dose of the compound preoperatively, followed by one or more orally administered doses of the compoundpostoperatively. Thus, it may be that the subject is administered an initial intravenous dose of the compound before a surgical procedure (e.g. a cardiac surgical procedure), followed by one or more orally administered doses of the compound after the surgical procedure (e.g. a cardiac surgical procedure).

[0159] In embodiments, the subject is administered an initial intravenous dose of the compound less than 6 hours from stroke onset, followed by one or more orally administered doses of the compound after the stroke.

[0160] The dosage of the pharmaceutically active agent administered with the composition of the invention will vary depending upon a number of factors including, for example the age, weight and gender of the subject suffering from the condition, the severity of the condition and the selected administration frequency.

[0161] A suitable dosage for intravenous, intraarterial and / or oral application can be readily determined by a physician. The dosage must be effective to achieve an improvement in the stroke symptoms. For example, the dosage must be effective to achieve an improvement in the functional deficits caused by the stroke, such as, but not limited to, arm weakness, and vision and speech disturbance. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount.

[0162] In embodiments, the compound is administered as a bolus dose (i.e. the entire daily dose is administered at once) or infusion. It may be that the compound is administered as a bolus dose or infusion over a period of less than 60 minutes. Thus, it may be that the compound is administered as a bolus dose over a period of less than 60 minutes. It may be that the compound is administered as an infusion over a period of less than 60 minutes. For example, over a period of up to 5 minutes, from 5 minutes to 15 minutes, from 15 minutes to 30 minutes, or from 30 minutes to 60 minutes. Preferably, the compound is administered as a bolus dose. It may be that the compound is administered in divided doses two or more times a day.

[0163] In some embodiments, it may be that the dose of the compound administered to the subject is sufficient to ensure a sustained therapeutic effect. It may be that a high dose of the compound is administered to the subject. Preferably, it may be that a high dose of the compound is administered to the subject to ensure a sustained therapeutic effect. Thus, it may be that the dose of the compound administered to the subject will be high enough to ensure that the serum concentration of the compound exceeds the IC50. For example, it may be that the serum concentration of the compound exceeds the IC50 by more than 10%, 20%, 30%, 40%, 50% or 100%.

[0164] In embodiments, it may be that the compound is administered to the subject at a dose of less than about 200 mg / kg. It may be that the compound is administered to the subject at a dose of less than about 150 mg / kg. It may be that the compound is administered to the subject at a dose of less than about 100 mg / kg. It may be that the compound is administered to the subject at a dose of from about 0.1 mg / kg to about 100 mg / kg. It may be that the compound is administered to the subject at a dose of from about 0.1 mg / kg to about 10 mg / kg. It may be that the compound is administered to the subject at a dose of from about 1 mg / kg to about 5 mg / kg, for example from about 1 mg / kg to about 2 mg / kg.

[0165] It may be that different dosing regimens may need to be employed to the subject to ensure a high serum concentration of the compound. Thus, it may be that the dosing regimen is selected from, but not limited to: bolus dose, IV (intravenous) bolus dose, intraarterial bolus dose, infusion, IV infusion, intraarterial infusion, oral administration, IV administration, or combinations thereof. In an embodiment, it may be that the compound is administered to the subject as a bolus dose only (i.e. the entire daily dose is administered at once). It may be that the bolus dose is administered to the subject via IV administration. As such, it may be that the compound is administered to the subject via IV bolus dose only. In another embodiment, it may be that the compound is administered to the subject as an infusion only. For example, it may be that the compound is administered to the subject as an IV infusion only. It may be that the infusion is administered over a suitable period, such as the periods defined herein. In another embodiment, it may be that the compound is administered to the subject as a bolus dose (e.g. via IV administration) followed by an infusion. In another embodiment, it may be that the compound is administered to the subject as a bolus dose (e.g. via IV administration) followed by oral administration. In another embodiment, it may be that the compound is administered to the subject via oral administration only. In other embodiments, it may be that the compound is administered to the subject as an intraarterial bolus dose or infusion, followed by IV administration or oral administration. For example, it may be that the compound is administered to the subject as an intraarterial bolus dose, followed by IV administration. It may be that the compound is administered to the subject as an intraarterial bolus dose, followed by oral administration. It may be that the compound is administered to the subject as an intraarterial infusion, followed by IV administration. It may be that the compound is administered to the subject as an intraarterial infusion, followed by oral administration. It will be understood that any suitable combination of dosing regimens described herein could be administered to the subject, as long as the combination of dosing regimens ensures a high serum concentration of the compound. It may be that the compound is administered as oral dose only.Combination Therapies

[0166] In embodiments, the compound of the invention is administered to the subject concomitantly with one or more additional therapeutic agent(s). Thus, it may be that the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject concomitantly with one or more additional therapeutic agent(s).

[0167] It may be that the compound is administered to the subject concomitantly within one additional therapeutic agent. It may be that the compound is administered to the subject concomitantly within two or more additional therapeutic agents. For example, it may be that the compound is administered to the subject concomitantly with three, four or five additional therapeutic agents.

[0168] In embodiments, it may be that the additional therapeutic agent is selected from: an anticoagulant, an antiplatelet agent (e.g. aspirin), an antithrombotic agent, a thrombolytic agent (e.g. a tissue-type plasminogen activator (t-PA) such as alteplase, or a fibrin-specific tissue-plasminogen activator such as tenecteplase), an anti-platelet agent, an anti-hypertensive, a lipid lowering agent, a cholesterol lowering agent, a glucose-lowering agent and a NA-1 antagonist (e.g. nerinetide).

[0169] It may be that the additional therapeutic agent is a thrombolytic agent, for example a t-PA. Thus, it may be that the compound is administered to the subject concomitantly with a t-PA.

[0170] It may be that the additional therapeutic agent is another neuroprotective agent. Thus, it may be that the compound is administered to the subject concomitantly with another neuroprotective agent.

[0171] In embodiments, it may be that the compound is administered to the subject prior to, after, or simultaneously with thrombolysis. Thus, it may be that the compound is administered to the subject prior to thrombolysis. It may be that the compound is administered to the subject after thrombolysis. It may be that the compound is administered to the subject simultaneously with thrombolysis.

[0172] In embodiments, it may be that the compound is administered to the subject prior to, after, or simultaneously with mechanical thrombectomy. Thus, it may be that the compound is administered to the subject prior to mechanical thrombectomy. It may be that the compound is administered to the subject after mechanical thrombectomy. It may be that the compound is administered to the subject simultaneously with mechanical thrombectomy.

[0173] In embodiments, it may be that the compound is administered intravenously to the subject prior to, after, or simultaneously with mechanical thrombectomy. Thus, it may be that the compound is administered intravenously to the subject prior to mechanicalthrombectomy. It may be that the compound is administered intravenously to the subject after mechanical thrombectomy. It may be that the compound is administered intravenously to the subject simultaneously with mechanical thrombectomy.

[0174] In embodiments, it may be that the compound is administered intraarterially to the subject prior to, after, or simultaneously with mechanical thrombectomy. Thus, it may be that the compound is administered intraarterially to the subject prior to mechanical thrombectomy. It may be that the compound is administered intraarterially to the subject after mechanical thrombectomy. It may be that the compound is administered intraarterially to the subject simultaneously with mechanical thrombectomy.

[0175] In embodiments, the tMCAO model described herein mimics thrombectomy.

[0176] In embodiments, advanced multi model imaging is used to identify salvageable brain tissue in stroke patients. It may be that advanced multi model imaging is used to identify salvageable brain tissue in stroke patients up to 6 h after stroke onset. It may be that advanced multi model imaging is used to identify salvageable brain tissue in stroke patients up to 12 h after stroke onset. It may be that advanced multi model imaging is used to identify salvageable brain tissue in stroke patients up to 18 h after stroke onset. It may be that advanced multi model imaging is used to identify salvageable brain tissue in stroke patients up to 24 h after stroke onset. It may be that advanced multi model imaging is used to identify salvageable brain tissue in stroke patients 24 h or longer after stroke onset. Thus, it may be that the compound of the invention is for use in the treatment of stroke in a subject, wherein advanced multi model imaging has been used to identify salvageable brain tissue. It may be that salvageable brain tissue is identified in said subject up to 6 h after stroke onset, and thus the compound is administered to said subject up to 6 h after stroke onset. It may be that salvageable brain tissue is identified in said subject up to 12 h after stroke onset, and thus the compound is administered to said subject up to 12 h after stroke onset. It may be that salvageable brain tissue is identified in said subject up to 18 h after stroke onset, and thus the compound is administered to said subject up to 18 h after stroke onset. It may be that salvageable brain tissue is identified in said subject up to 24 h after stroke onset, and thus the compound is administered to said subject up to 24 h after stroke onset. It may be that salvageable brain tissue is identified in said subject 24 h or longer after stroke onset, and thus the compound is administered to said subject 24 h or longer after stroke onset. In this embodiment, it may be that the compound is administered to said subject either alone, or in combination with other treatments described herein. For example, it may be that the compound is administered to said subject in combination with one or more additional therapeutic agent(s) described herein. It may be that the compound is administered to saidsubject in combination with t-PA. It may be that the compound is administered to said subject in combination with thrombectomy.Subject

[0177] The compounds of the invention are suitable for use in the treatment of a subject affected by any of the conditions or disorders described herein.

[0178] In embodiments, the subject may be a warm-blooded mammal. In particular embodiments, the subject treated is a human.

[0179] In embodiments, the subject is at a high risk of a stroke. For example, it may be that the subject has diabetes, high blood pressure, atrial fibrillation, heart disease, an aneurysm, AVM, atherosclerosis, or is overweight. It may be that the subject has recently had heart surgery.

[0180] In embodiments, the subject is overweight. Thus, it may be that the subject has a body mass index of about 25 kg / m2to about 30 kg / m2. It may be that the subject has a body mass index greater than or equal to about 30 kg / m2. It may be that the subject has a body mass index of about 30 kg / m2to about 35 kg / m2. It may be that the subject has a body mass index of about 35 kg / m2to about 40 kg / m2. It may be that the subject has a body mass index greater than or equal to about 40 kg / m2.

[0181] In embodiments, the subject is an adult human (aged 18 years or more). It may be that the subject is 45 or more years old. It may be that the subject is 55 or more years old. It may be that the subject is 65 or more years old.

[0182] In embodiments, the subject has diabetes. It may be that the subject has high blood pressure. Thus, it may be that the subject as a blood pressure of from about 135 / 85 mmHg or more. It may be that the subject as a blood pressure of from about 140 / 90 mmHg or more.

[0183] In embodiments, the subject has high cholesterol. Thus, it may be that the subject has a total cholesterol of about 5 mmol / L or more. It may be that the subject has a total cholesterol to HDL cholesterol ratio of about 6 mmol / L or more.

[0184] In embodiments, the subject has never previously had a stroke. It may be that the subject has experienced one or more TIAs. It may be that the subject has previously had a stroke. Thus, it may be that the stroke is a recurrent stroke.EXAMPLES

[0185] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Starting materials were purchased from commercial sources or synthesised according to the methods described herein or using literature procedures.AbbreviationsBBB - Blood Brain BarrierCCA - common carotid arteryECA - external carotid artery h - hoursICA - internal carotid arteryMCA - middle cerebral artery min - minutesMRI - Magnetic Resonance Imaging pMCAO - Permanent Middle Cerebral Artery Occlusion tMCAO - Transient Middle Cerebral Artery OcclusionROI - regions of interestTTC - 2,3,5-Triphenyltetrazolium chlorideMaterials

[0186] C57bl / 6J mice, purchased from Charles River, UK were used. The use of animals and aseptic surgical procedures were in accordance with the guidelines stated under a licence obtained from the Home Office subject to the Animals (Scientific Procedures; Act, 1986).Methods and Analytical Methods tMCAO:

[0187] After induction of anaesthesia (inhalation of 5% isofluorane for induction then 1.5 % isofluorane for maintenance throughout the surgical procedure), a midline incision was made on the ventral side of the neck and the left common carotid artery (CCA) was isolated and ligated. Another ligature was tied on the left external carotid artery (ECA) and a loose knot was tied onto the internal carotid artery (ICA) as well as CCA just below the bifurcation. A veryfine incision was made on the lower end of CCA and a monofilament (Doccol Corporation, Sharon, MA, USA) was advanced approximately 9 mm distal to the bifurcation into the ICA until it reached the distal end of middle cerebral artery (MCA). The monofilament was kept in place for 45-60 minutes, while the animals were kept under anaesthesia. After this period the monofilament was withdrawn and reperfusion was allowed to take place. pMCAO:

[0188] After induction of anaesthesia (inhalation of 5% isofluorane for induction then 1.5 % isofluorane for maintenance throughout the surgical procedure) the left MCA was exposed by a small craniotomy. The MCA was then coagulated with electrocoagulation forceps proximal and distal to the bifurcation.Obese mice:

[0189] Mice underwent a high fat diet (60% fat) for 4 months prior to ischemia.Infarct volume:

[0190] 200 mg / kg of AZD1236 (dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water) was administered to the mice at 2, 4, or 6 hours post ischaemia onset, and a further 200 mg / kg of AZD1236 (dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water) was administered to the mice at 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV (intravenous) bolus immediately followed by 100 mg / kg p.o (per os (oral administration by gavage)). The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o. The mice were then sacrificed at 48 hours, and infarct volume was determined.

[0191] For the vehicle group, 200 pL of the vehicle (2-hydroxypropyl-beta- cyclodextrine 40% w / w in distilled water) was administered to the mice at 2, 4, or 6 hours post ischaemia onset, and a further 200 pL of the vehicle was administered to the mice at 24 hours post ischaemia onset. The initial 200 pL dose of the vehicle (at 2, 4, or 6 hours) was administered as a 100 pL IV bolus immediately followed by 100 pL p.o. The second 200 pL dose of the vehicle (at 24 hours) was administered by p.o. The mice were then sacrificed at 48 hours, and infarct volume was determined.

[0192] Infarct volume was evaluated with histology analysis using TTC staining.

[0193] For histology: 48 hours post ischemia, mice were deeply anaesthetized with5% isoflurane, brains were removed and coronal slices with a thickness of 1 mm wereprepared. Brain slices were immersed in 2% TTC (2,3,5-Triphenyltetrazolium chloride) solution and incubated at 37 °C for 20 min. The area of infarction was traced and measured using image J analysis software. The infarct area was also corrected for edema: [1 -(total ipsilateral hemisphere-infarct region) / total contralateral hemisphere]X100. Total infarct volume was calculated as the sum of all infarct areas multiplied by each section thickness.Neurological outcome (post ischaemia onset):

[0194] 200 mg / kg of AZD1236 (dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water) was administered to the mice at 2, 4, or 6 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 (dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water) administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0195] For the vehicle group, 200 pL of the vehicle (2-hydroxypropyl-beta- cyclodextrine 40% w / w in distilled water) was administered to the mice at 2, 4, or 6 hours post ischaemia onset, followed by 200 pL of the vehicle administered to the mice daily by p.o. for 7 days. The initial 200 pL dose of the vehicle (at 2, 4, or 6 hours) was administered as a 100 pL IV bolus immediately followed by 100 pL p.o.

[0196] Neurological outcome was then evaluated using the Garcia scale.

[0197] A Garcia test with a 18-point score was performed at different intervals post ischemia onset, to assess motor and sensory functions. Mice were scored on their spontaneous activity (0-3), symmetry of limb movement (0-3), forelimb outstretching (0-3), climbing and grip strength (0-3), symmetry of body proprioception (0-3), and sensory function of vibrissae (0-3). The Garcia scale is represented as the sum of score in each test. In this scale, a lower score indicates a more severe stroke outcome.Pain behaviours:

[0198] 200 mg / kg of AZD1236 (dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water) was administered to the mice at 2, 4, or 6 hours post ischaemia onset, followed by 200 mg / kg of AZD1236 (dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water) administered daily by p.o. for 7 days. The initial 200 mg / kg dose of AZD1236 (at 2, 4, or 6 hours) was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o.

[0199] For the vehicle group, 200 pL of the vehicle (2-hydroxypropyl-beta- cyclodextrine 40% w / w in distilled water) was administered to the mice at 2, 4, or 6 hours post ischaemia onset, followed by 200 pL of the vehicle administered to the mice daily by p.o. for 7 days. The initial 200 pL dose of the vehicle (at 2, 4, or 6 hours) was administered as a 100 pL IV bolus immediately followed by 100 pL p.o.

[0200] Pain behaviours were then evaluated by measuring development of allodynia using the von Frey test, and development of hyperalgesia using the thermal test.

[0201] Von Frey test: Allodynia was measured by hindpaw application of calibrated von Frey filaments to assess paw withdrawal threshold. The number of positive responses to 2 grams von Frey filament was recorded as the withdrawal threshold and a cut off of 10 applications was used. In this test, a higher number of withdrawal responses indicates a more severe post-stroke pain.

[0202] Thermal test: Hypersensitivity was evaluated by hindpaw application of radiant heat stimuli for measurements of paw withdrawal latency. The time taken to withdraw from the heat stimulus was recorded as the withdrawal latency. The intensity of the light source was adjusted to produce withdrawal latencies of 7-9 seconds in naive animals and a cut off time of 10 seconds was used. In this test, a lower withdrawal latency indicates a more severe poststroke pain.Blood Brain Barrier (BBB) integrity:

[0203] Blood Brain Barrier integrity was measured by extravasation of Evans Blue dye and MRI analysis.For Evan’s Blue extravasation:

[0204] 200 mg / kg of AZD1236 (dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water) was administered to the mice at 2 hours post ischaemia onset, and a further 200 mg / kg of AZD1236 (dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water) was administered to the mice at 24 hours post ischaemia onset. The initial 200 mg / kg dose of AZD1236 (at 2 hours) was administered as a 100 mg / kg IV (intravenous) bolus immediately followed by 100 mg / kg p.o (per os (oral administration by gavage)). The second 200 mg / kg dose of AZD1236 (at 24 hours) was administered by p.o.

[0205] For the vehicle group, 200 pL of the vehicle (2-hydroxypropyl-beta- cyclodextrine 40% w / w in distilled water) was administered to the mice at 2 hours post ischaemia onset, and a further 200 pL of the vehicle was administered to the mice at 24 hourspost ischaemia onset. The initial 200 pL dose of the vehicle (at 2 hours) was administered as a 100 pL IV bolus immediately followed by 100 pL p.o. The second 200 pL dose of the vehicle (at 24 hours) was administered by p.o.

[0206] 48 hours post tMCAO or pMCAO, the mice then received an intravenous injection of 2% Evan’s Blue injection. 45 minutes after Evan’s blue administration, brain was collected and stored in formamide at 60 °C for 72 hours. Following incubation with formamide, concentration of Evan’s Blue was analysed by spectrophotometry at 620 nm.For MRl analysis:

[0207] 200 mg / kg of AZD1236 (dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water) was administered to the mice at 2 hours post ischaemia onset. The 200 mg / kg dose of AZD1236 was administered as a 100 mg / kg IV (intravenous) bolus immediately followed by 100 mg / kg p.o (per os (oral administration by gavage)).

[0208] For the vehicle group, 200 pL of the vehicle (2-hydroxypropyl-beta- cyclodextrine 40% w / w in distilled water) was administered to the mice at 2 hours post ischaemia onset. The 200 pL dose of the vehicle was administered as a 100 pL IV bolus immediately followed by 100 pL p.o.

[0209] 24 hours post tMCAO, the mice then underwent MRl analysis using a 7T scanner with T1 and T2 maps acquired (RARE-VTR) (brain slice thickness 0.75mm; in-plane resolution, 0.25x0.25 mm), pre- and post-gadolinium IP injection (DOTAREM, 100 pL). The second RARE-VTR was started -30 min post IP injection. T1 and T2 maps were analysed using custom Matlab code and drawing regions of interest (ROI). As will be understood, T1- weighted MRl enhances the signal of the fatty tissue and suppresses the signal of water, and T2-weighted MRl enhances the signal of the water.Intracerebral Haemorrhage (ICH):

[0210] 4% isoflurane was used for induction of anaesthesia, then 1.5% isoflurane was used for maintenance throughout the surgical procedure. After aseptically preparation of the surgical site, mice were placed on a stereotactic frame connected to an automated injection minipump with attached a Hamilton syringe. After identification of the bregma a small craniotomy was performed for administration of 0.075LI of collagenase into the left striatum at a rate of 1 pl / min. The syringe was slowly withdrawn 10 min after the injection. Following ICH induction, bone wax was applied to the skull, the wound was sutured, and mice were allowed to recover from anaesthesia in a nursing box at 35 °C for approximately 60 min prior to returnto their home cages. AZD1236 or vehicle were administered at 2, 4, or 6 hrs post ICH induction.

[0211] AZD1236 was dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water. The corresponding vehicle used was 2-hydroxypropyl-beta-cyclodextrine 40% w / w in distilled water.

[0212] Both vehicle and AZD1236 were administered by intravenous bolus (to a maximum concentration of 100 mg / kg) and per os (per os (oral administration by gavage)) (to a maximum concentration of 200 mg / kg). The initial 200 mg / kg dose of AZD1236 was administered as a 100 mg / kg IV (intravenous) bolus immediately followed by 100 mg / kg p.o. (per os). From 24hr from haemorrhage induction, all the following 200 mg / kg doses of AZD1236 were administered by p.o. Similarly for the vehicle.Haemorrhage volume histology analysis:

[0213] 24 hours post ICH, mice were deeply anaesthetized with 5% isoflurane, brains were removed and coronal slices with a thickness of 1 mm were prepared. Brain slices were mounted on slices and pictures were taken. The area of haemorrhage was traced and measured using image J analysis software. The haemorrhage area was corrected for oedema and the total haemorrhage volume was calculated as the sum of all haemorrhage areas multiplied by each section thickness using the following formula:[1-(total ipsilateral hemisphere-haemorrhage region) / total contralateral hemisphere]X100Statistical Analysis:

[0214] Statistical analysis was performed using the t-test for TTC staining and neurological outcome. For MRI analysis ANOVA test followed by a Bonferroni post-hoc test was used, while for pain behaviours 2way ANOVA was used.Example 1 - Permanent Middle Cerebral Artery Occlusion (pMCAO)

[0215] Young male mice received the pMCAO procedure, and infarct volume, neurological outcome, and BBB integrity were determined as outlined in the methods above.

[0216] AZD1236 significantly reduced stroke volume in comparison to the vehicle (2- hydroxypropyl-beta-cyclodextrine 40% w / w in water) when delivered at 2 and 4 hours (but not at 6 hours) post ischaemic onset. This can be seen from Figure 1 , whereby AZD1236 timedependently reduced infarct volume in young male mice, 48 hours post pMCAO (as evaluated by the histology analysis using TTC staining, detailed above) (N= 7-10 per group).

[0217] AZD1236 also elicited significant improvement in the functional outcome over a period of 28 days when delivered at 2 and 4 hours (but not at 6 hours) post ischaemia. This can be seen from Figure 2, whereby AZD1236 time dependently reduced neurological deficits in young male mice with pMCAO (as evaluated by the Garcia scale, detailed above) (N= 11- 16 per group).

[0218] AZD1236 also significantly reduced BBB damage in comparison to the vehicle.This can be seen from Figure 3, whereby AZD1236 reduced BBB breakdown 48 hours following pMCAO (as measured by extravasation of Evans Blue dye, detailed above) (N= 6- 11 per group).Young (~25 weeks old) female mice:

[0219] Young female mice received the pMCAO procedure, and infarct volume, and neurological outcome were determined as outlined in the methods above.

[0220] AZD1236 significantly reduced infarct volume in comparison to vehicle when delivered at 2 hours post ischaemic onset. This can be seen from Figure 4, whereby AZD1236 significantly reduced infarct volume in young female mice, 48 hours post pMCAO (as evaluated by the histology analysis using TTC staining, detailed above) (N= 11-12 per group).

[0221] AZD1236 also elicited significant improvement in the functional outcome in young female mice over a period of 28 days when delivered at 2 and 4 hours (but not at 6 hours) post ischaemia, in young female mice. This can be seen in Figure 5, whereby AZD1236 time dependently reduced neurological deficits in young female mice with pMCAO (as evaluated by the Garcia scale, detailed above) (N= 10-11 per group).Acted (~ 67 weeks old) male and female mice:

[0222] Aged male and female mice received the pMCAO procedure, and infarct volume, and neurological outcome were determined as outlined in the methods above.

[0223] AZD1236 significantly reduced infarct volume in comparison to vehicle when delivered at 2 hours post ischaemic onset, in both aged male and female mice. This can be seen in Figures 6 and 8, whereby AZD1236 significantly reduced infarct volume in aged male and female mice, 48 hours post pMCAO, respectively (as evaluated by the histology analysis using TTC staining, detailed above) (N =5 per group).

[0224] In aged male and female mice, AZD1236 elicited significant improvement in the functional outcome over a period of 28 days when delivered at 2 hours post ischaemia. Thiscan be seen in Figures 7 and 9, whereby AZD 1236 significantly improved neurological deficits in aged male and female mice with pMCAO, respectively (as evaluated by the Garcia scale, detailed above) (N= 10-14 per group).Example 2 - Transient Middle Cerebral Artery Occlusion (tMCAO)

[0225] Young male mice received the tMCAO procedure, and infarct volume, neurological outcome, and BBB integrity were determined as outlined in the methods above.

[0226] AZD1236 significantly reduced infarct volume in comparison to the vehicle (2- hydroxypropyl-beta-cyclodextrine 40% w / w in water) when delivered at 2 and 4 hours (but not at 6 hours) post ischaemic onset This can be seen from Figure 10, whereby AZD1236 time dependently reduced infarct volume in young male mice, 48 hours post tMCAO (as evaluated by the histology analysis using TTC staining, detailed above) (N= 8-10 per group).

[0227] AZD1236 elicited significant improvement in the functional outcome over a period of 28 days when delivered at 4 hours (but not at 6 hours) post ischaemia. This can be seen from Figure 11 , whereby AZD1236 time dependently reduces neurological deficits in young male mice with tMCAO (as evaluated by the Garcia scale, detailed above) (N= 15-16 per group).

[0228] AZD1236 significantly reduced BBB damage in comparison to the vehicle. This can be seen from Figure 12, whereby AZD1236 reduced BBB breakdown 48 hours following tMCAO in young male mice (as measured by extravasation of Evans Blue dye, detailed above) (N= 6-10).

[0229] AZD1236 also increased blood-brain barrier integrity in young male mice 24 hours post tMCAO, compared to mice treated with vehicle (see, Figure 21) (as evaluated by MRI analysis, detailed above) (N= 4-5 per group).Young (~25 weeks old) female mice:

[0230] Young female mice received the tMCAO procedure, and infarct volume, and neurological outcome were determined as outlined in the methods above.

[0231] AZD1236 significantly reduced infarct volume in young female mice with tMCAO in comparison to the vehicle when delivered at 2 and 4 hours post ischaemic onset (see, Figure 13) (as evaluated by the histology analysis using TTC staining, detailed above) (N=5-7 per group).

[0232] AZD1236 elicited significant improvement in the functional outcome over a period of 28 days when delivered at 2 and 4 hours post ischaemia. This can be seen in Figure14, whereby AZD1236 time dependently reduced neurological deficits in young female mice with tMCAO (as evaluated by the Garcia scale, detailed above) (N=17-20 per group).Aged (~ 67 weeks old) male and female mice:

[0233] Aged male and female mice received the tMCAO procedure, and infarct volume, and neurological outcome were determined as outlined in the methods above. AZD1236 significantly reduced infarct volume in comparison to the vehicle when delivered at 2 hours post ischaemic onset, in both aged male and female mice. See, Figures 15 and 17, whereby AZD1236 significantly reduced infarct volume in both aged male and female mice 48 hours post tMCAO, respectively (as evaluated by the histology analysis using TTC staining, detailed above) (N= 6-8 per group).

[0234] In aged male and female mice, AZD1236 elicited significant improvement in the functional outcome over a period of 28 days when delivered at 2 hours post ischaemia. See, Figures 16 and 18, whereby AZD1236 improved neurological deficits in both aged male and female mice with tMCAO, respectively (as evaluated by the Garcia scale, detailed above) (N=11 -18 per group).Example 3 - Obese Mice

[0235] Obese male mice received the pMCAO or tMCAO procedure, and infarct volume or neurological outcome was determined as outlined in the methods above.

[0236] AZD1236 significantly reduced the infarct (lesion) volume in comparison to the vehicle (2-hydroxypropyl-beta-cyclodextrine 40% w / w in water) when delivered at 2 hours post ischaemic onset. This can be seen from Figures 19 and 20, whereby AZD1236 reduced lesion volume in obese male mice, 48 hours post pMCAO (see, Figure 19) or tMCAO (see, Figure 20) (as evaluated by the histology analysis using TTC staining, detailed above) (N=10 per group).

[0237] AZD1236 also greatly improved neurological deficits in obese male mice with pMCAO (see, Figures 19) or tMCAO (see, Figure 20) (as evaluated by the Garcia scale, detailed above) (N= 17-20 per group).Example 4 - Pharmacokinetic (PK) Data

[0238] Young male and female mice, old male and female mice, and obese male mice received the tMCAO procedure, as outlined above. 200 mg / kg of AZD1236 (dissolved in 2- hydroxypropyl-beta-cyclodextrine 40% w / w in water) was then administered to young male and female mice, and old male and female mice 2 hours post ischaemia onset. The 200 mg / kg dose of AZD1236 was administered as a 100 mg / kg IV bolus immediately followed by 100 mg / kg p.o. 100 mg / kg of AZD1236 (dissolved in 2-hydroxypropyl-beta-cyclodextrine 40% w / win water) was administered to obese male mice, 2 hours post ischaemia onset. The 100mg / kg dose of AZD1236 was administered as IV bolus.

[0239] AZD1236 brain and plasma concentrations remained elevated for up to 6 hours in both young and aged male and female mice, when injected at 2 hours post tMCAO onset (see, Figures 22 and 23, respectively). AZD1236 brain concentrations remained elevated for up to 6 hours in obese male mice, when injected at 2 hours post tMCAO onset (see, Figure 22A). However, AZD1236 plasma concentrations did not remain elevated in obese male mice, when injected at 2 hours post tMCAO onset (see, Figure 22B) (N= 4-6 per group).Example 5 - Post-stroke Pain

[0240] Young male and female mice received the pMCAO procedure, and were evaluated for pain behaviour as outlined in the methods above.

[0241] AZD1236 time dependently inhibited development of mechanical allodynia in young male and female mice with pMCAO (see, Figures 24 and 26, respectively) (as evaluated by the Von Frey test, detailed above) (N=10-11 per group).

[0242] AZD1236 time dependently also inhibited the development of thermal hyperalgesia in young male and female mice with pMCAO (see, Figures 25 and 27, respectively) (as evaluated by the Thermal test, detailed above) (N=10-11 per group).Example 6 - Intracerebral Haemorrhage (ICH)

[0243] Young male mice received the ICH procedure. Haemorrhage volume histology analysis was determined as outlined in the methods above.

[0244] AZD1236 significantly reduced haemorrhage volume in comparison to the vehicle when delivered at 2h, 4h and 6h post collagenase administration (see, Figure 28).

[0245] As demonstrated by the examples above, AZD1236 is effective in the treatment of both ischaemic and haemorrhagic strokes.References1. Lee, S. et al., UK stroke incidence, mortality and cardiovascular risk management 1999-2008: time-trend analysis from the General Practice Research Database. BMJ Open, 2011. 1(2): p.e000269.2. Majid, A., Neuroprotection in stroke: past, present, and future. ISRN Neurol, 2014. 2014: p.515716.3. Chang, J. J et al., The Role of Matrix Metalloproteinase Polymorphisms in Ischemic Stroke. Int J Mol Sci, 2016. 17(8).4. Raj an i kant, G . K. , et al. , Carnosine is neuroprotective against permanent focal cerebral ischemia in mice. Stroke, 2007. 38(11): p. 3023-31.5. Chaturvedi, M. and L. Kaczmarek, Mmp-9 inhibition: a therapeutic strategy in ischemic stroke. Mol Neurobiol, 2014. 49(1): p. 563-73.6. Turner, R.J. and F.R. Sharp, Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke. Front Cell Neurosci, 2016. 10: p. 56.7. Chelluboina, B., et al., Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage. Sci Rep, 2015. 5: p. 9504.8. Fagan, S.C., L.E. Cronic, and D.C. Hess, Minocycline development for acute ischemic stroke. Transl Stroke Res, 2011. 2(2): p. 202-8.9. Romanic, A.M., et al., Matrix metalloproteinase expression increases after cerebral focal ischemia in rats. Stroke, 1998. 29(5): p. 1020-30.10. Matsumoto, S., etal., Expression and localization of matrix metalloproteinase-12 in the aorta of cholesterol-fed rabbits. Am J Pathol, 1998. 153(1): p. 109-19.11. Chandler, S., et al., Macrophage metalloelastase degrades matrix and myelin proteins and processes a tumour necrosis factor-alpha fusion protein. Biochem Biophys Res Commun, 1996. 228(2): p. 421-9.12. Hiller, O., et al., Matrix metalloproteinases collagenase-2, macrophage elastase and membrane type 1 -matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII. J Biol Chem, 2000. 275(42): p. 33008-13.13. https: / / openinnovation.astrazeneca.com / clinical-research / clinical- molecules / azd1236.html14. Dahl R,et al., Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate / severe COPD: a randomised controlled trial. Pulm Pharmacol Ther. 2012 Apr;25(2): 169-7715. Magnussen H, et al., Safety and toierabiiity of an oral MMP-9 and -12 inhibitor, AZD1236, in patients with moderate-to-severe COPD: a randomised controlled 6- week trial. Pulm Pharmacol Ther. 2011 Oct;24(5):563-70.

Claims

CLAIMS1 . A compound of Formula (I), or a pharmaceutical salt thereof:for use in the treatment of stroke in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

2. The compound for use of claim 1 , wherein the stroke is acute ischaemic stroke.

3. The compound for use of claim 1 , wherein the stroke is haemorrhagic stroke.

4. The compound for use of any one of claims 1 to 3, wherein the treatment reduces poststroke neurological deficit.

5. The compound for use of any one of claims 1 to 4, wherein the treatment prevents or inhibits one or more of brain edema, haemorrhagic transformation, and neuroinflammation.

6. The compound for use of any one of claims 1 to 5, wherein the compound is administered to the subject concomitantly with one or more additional therapeutic agent, optionally wherein the additional therapeutic agent is selected from: an anticoagulant, an antiplatelet agent, an antithrombotic agent, a thrombolytic agent (e.g. a tissue-type plasminogen activator such as alteplase, or a fibrin-specific tissueplasminogen activator such as tenecteplase), an anti-platelet agent, an antihypertensive, a lipid lowering agent, a cholesterol lowering agent, a glucose-lowering agent and a NA-1 antagonist (e.g. nerinetide).

7. The compound for use of any one of claims 1 to 6, wherein the compound is administered to the subject concomitantly with a suitable neuroprotective agent.

8. The compound for use of any one of claims 1 to 7, wherein the compound is administered to the subject prior to, after, or simultaneously with thrombolysis.

9. The compound for use of any one of claims 1 to 8, wherein the compound is administered to the subject prior to, after, or simultaneously with mechanical thrombectomy either intravenously, orally or intra arterially.

10. A compound of Formula (I), or a pharmaceutical salt thereof:for use in the treatment of post-stroke pain in a subject, wherein the compound is administered to the subject less than 6 hours from stroke onset.

11. The compound for use of claim 10, wherein the post-stroke pain is post-stroke neuropathic pain.

12. The compound for use of claim 10 or claim 11 , wherein the post-stroke pain is allodynia (e.g. mechanical allodynia) or hyperalgesia (e.g. thermal hyperalgesia); preferably wherein the post-stroke pain is mechanical allodynia.

13. The compound for use of any one of claims 1 to 12, wherein the compound is administered 4 hours or less from stroke onset.

14. The compound for use of any one of claims 1 to 12, wherein the compound is administered 2 hours or less from stroke onset.

15. The compound for use of any one of claims 1 to 14, wherein the compound is administered to the subject intravenously.

16. The compound for use of claim 15, wherein the compound is administered as a bolus dose or infusion over a period of less than 60 minutes, preferably wherein the compound is administered as a bolus dose.

17. The compound for use of claim 15 or claim 16, wherein the compound is administered to the subject at a dose of from about 0.1 mg / kg to about 10 mg / kg.

18. The compound for use of any one of claims 1 to 17, wherein the subject is administered an initial intravenous dose of the compound followed by one or more orally administered doses of the compound, for example wherein the orally administered doses of the compound are administered once or twice daily.

19. A compound of Formula (I), or a pharmaceutical salt thereof:for use in preventing or reducing the risk of iatrogenic stroke in a subject.

20. The compound for use of claim 19, wherein the iatrogenic stroke is caused by or associated with a surgical procedure selected from a cardiac surgical procedure (e.g. cardiac valve surgery (such as transcatheter aortic valve replacement (TAVR) or transcatheter aortic valve implantation (TAVI), or coronary artery bypass grafting), coiling or stenting of an aneurysm and an extracranial or intracranial endovascular procedure (e.g. stenting)).

21. The compound for use of claim 19 or claim 20, wherein the compound is administered to the subject prior to the commencement of a surgical procedure.

22. The compound for use of any one of claims 19 to 21, wherein the compound is administered to the subject intravenously.

23. The compound for use of any one of claims 1 to 22, wherein the subject is a human.

24. The compound for use of claim 23, wherein the subject is obese, for example wherein the subject has a body mass index greater than or equal to about 30 kg / m2.

25. The compound for use of claim 23 or 24, wherein the subject is 55 or more years old.

Images