Cannabinoid aminoquinone compounds as activators of AMPK / sirtuin-1 pathway

Abstract

Present invention relates to cannabinoid aminoquinone compounds for use in the prevention and / or treatment of conditions mediated by AMPK / Sirtruin1 pathway, in particular associated with vascular senescence. The invention also discloses further cannabinoid aminoquinone compounds and first and further medical uses thereof, along with pharmaceutical compositions comprising the same.

Description

[0001] DESCRIPTION

[0002] CANNABINOID AMINOQUINONE COMPOUNDS AS ACTIVATORS OF AMPK / SIRTUIN-1 PATHWAY

[0003] TECHNICAL FIELD

[0004] The present application relates to cannabinoid aminoquinone compounds and medical uses thereof. More specifically, novel cannabinoid aminoquinone compounds are provided as well as uses of cannabinoid aminoquinone compounds as activators of the AMPK / Sirtuin 1 pathway and, more, for treatment and / or prevention of diseases that can benefit from the activation of such pathways.

[0005] BACKGROUND ART

[0006] AMPK (5' adenosine monophosphate-activated protein kinase) and Sirtl (sirtuin 1) are pivotal regulators of cellular metabolism and stress responses, often working synergistically to maintain energy balance, enhance mitochondrial function, and promote overall health. AMPK functions as an energy sensor activated by a high AMP / ATP ratio during low-energy states. Once activated, it stimulates glucose uptake, fatty acid oxidation, mitochondrial biogenesis, and autophagy, while suppressing energy-intensive anabolic pathways such as lipogenesis and protein synthesis (Hardie et al., 2012). Similarly, Sirtl, a NAD+-dependent deacetylase, modulates transcription factors and enzymes to promote fatty acid oxidation, glucose homeostasis, mitochondrial function, DNA repair, and resistance to oxidative stress (Imai & Guarente, 2014). Additionally, Sirtl reduces inflammation and delays cellular senescence (Li et al., 2011).

[0007] The interconnection between these pathways amplifies their biological effects. AMPK activation increases intracellular NAD+ levels, stimulating Sirtl activity, while Sirtl enhances AMPK by deacetylating and activating LKB1, an upstream kinase of AMPK (Rodriguez et al., 2021). AMPK-driven Sirtl activation modulates downstream targets, highlighting their overlapping roles in energy metabolism and cellular homeostasis (Price et al., 2012). Sirtl expression is strongly linked to lifespan and is significantly reduced with aging, as observed in both animal models and humans. This reduction mediates age-related senescence (Canto et al., 2009). Sirtl dysfunction contributes to various chronic and age- related diseases, making it a critical target for therapeutic interventions aimed at extending healthspan and slowing disease progression.

[0008] Therefore, AMPK and Sirtl activators represent a promising therapeutic strategy for a wide range of chronic and age-related diseases. These activators offer innovative solutions for various diseases and indications.

[0009] The problem was thus the provision of AMPK and Sirtl activators. This problem is solved by the provision of compounds as disclosed herein that can be used in the treatment of various diseases.

[0010] SUMMARY OF INVENTION

[0011] The present disclosure is based on cannabinoid aminoquinone compounds with exhibits activity in modulating the AMPK / Sirtl pathways. Hence, these compounds prevent endothelial cells damage and senescence.

[0012] Thus, the present invention relates to a compound comprising Formula I,

[0013] (Formula I) wherein

[0014] R1is a Ci-Ce unbranched or branched alkyl that is optionally substituted at its terminus with a group selected from a 5- or 6-membered heterocycloalkyl, a phenyl, an amino group, NH(CO)CH3, OH, or C1-C3 alkoxy, wherein the 5- or 6-membered heterocycloalkyl can be optionally substituted with C1-C4 alkyl; and R2is CH3 or CH2CH2CH3. is provided for use in the treatment or prevention of chronic venous insufficiency, Raynaud’s syndrome, peripheral microangiopathies, non-cancerous vascular malformations, acute peripheral arterial occlusion, metabolic bone disorders, sarcopenia, fracture healing, osteoarthritis, vitiligo, rosacea, atopic dermatitis, melasma, skin aging, non-fibrotic chronic kidney disease, glomerular disorders, renal tubular acidosis, mitochondrial myopathies, age-related macular degeneration, rare vascular disorders, frailty syndrome, inherited metabolic and vascular disorders.

[0015] The treatment or prevention may include the activation of the AMPK / Sirtl pathways. The diseases to be treated with the compounds as disclosed herein may be associated with cellular senescence.

[0016] In some embodiments the heterocycloalkyl is a five- or six-membered ring containing one or more heteroatoms selected from N, O, and S. In some embodiments the heterocycloalkyl may be optionally substituted. In some embodiments the heterocycloalkyl is tetrahydrofuran, pyrrolidine, or thiophene. In other embodiments the heterocycloalkyl is piperidine, pyridine, or tetrahydrothiopyran. In yet other embodiments the heterocycloalkyl is 1,4 dioxane, imidazole, pyrazole, pyrimidine, pyridazine, pyrazine, oxazole, thiazole, or morpholine. In some embodiments.

[0017] The method comprises administering to the mammal a compound comprising Formula I in a manner sufficient to prevent and / or to treat the above indicated diseases.

[0018] The present invention also specifically discloses cannabinoid aminoquinone compounds of Formula I such as for example compounds X-XII and pharmaceutical compositions containing the same, along with their first and further medical uses.

[0019] DETAILED DESCRIPTION OF THE INVENTION

[0020] As used herein, the term “excipient” refers to an inert ingredient added to a pharmaceutical composition. Said excipient may be a diluent, as a way of example. As used herein, the term “derivative” refers to a compound that is derived from the compound of the invention and includes, without limitation, esters, salts, solvates and hydrates.

[0021] As used herein, the term “cosolvents” refers to compounds added to a primary solvent of a pharmaceutical composition in small amounts to increase the solubility of a poorly soluble compound.

[0022] As used herein, the term “surfactants” refers to amphiphilic compounds added to a pharmaceutical composition which are used to solubilize poorly soluble drugs, improve their dissolution profile, promote permeation, improve drug delivery and enhance stabilization.

[0023] As used herein, the term “humectants” refers to compounds added to a pharmaceutical composition intended to keep moisture in the composition.

[0024] As used herein, the term “emollients” refers to compounds added to a pharmaceutical composition than when applied to the skin, they soothe and hydrate it.

[0025] As used herein, the term “preservatives” refers to compounds added to a pharmaceutical composition to protect them from chemical change or microbial action

[0026] As used herein, the term “stabilizers” refers to compounds added to a pharmaceutical composition to improve the stability and efficacy of drugs.

[0027] As used herein, the term “antioxidants” refers to compounds added to a pharmaceutical composition to inhibit oxidation, a chemical reaction that can produce free radicals.

[0028] As used herein, the term “solvates” refers to complexes formed by the attachment of solvent molecules to that of a solute.

[0029] As used herein, the terms “vascular aging”, “vascular senescence”, “endothelial senescence”, “endothelial cells senescence” or “vascular endothelial senescence”, must be interpreted as synonyms. For example, endothelial cells senescence may be measured as indicated by the examples.

[0030] As used herein, the terms “arteriogenesis”, “artery growth”, “arterial vascular growth”, must be interpreted as synonyms.

[0031] The present invention concerns a compound of formula (I)

[0032] (Formula I) or derivatives thereof, particularly pharmaceutically acceptable salts, esters or solvates thereof, wherein,

[0033] R1is a Ci-Ce unbranched or branched alkyl that is optionally substituted at its terminus with a group selected from a 5- or 6-membered heterocycloalkyl, a phenyl, an amino group, NH(C0)CH3, OH, or C1-C3 alkoxy, wherein the 5- or 6-membered heterocycloalkyl can be optionally substituted with C1-C4 alkyl; and

[0034] R2is CH3or CH2CH2CH3; for use in the treatment or prevention of chronic venous insufficiency, Raynaud’s syndrome, peripheral microangiopathies, non-cancerous vascular malformations, acute peripheral arterial occlusion, metabolic bone disorders, sarcopenia, fracture healing, osteoarthritis, vitiligo, rosacea, atopic dermatitis, melasma, skin aging, non-fibrotic chronic kidney disease, glomerular disorders, renal tubular acidosis, mitochondrial myopathies, age-related macular degeneration, rare vascular disorders, frailty syndrome, inherited metabolic and vascular disorders

[0035] The treatment or prevention may include the activation of the AMPK / Sirtl pathways One preferred embodiment of the invention is a compound of formula (I) for use in the prevention and / or treatment of vascular endothelial senescence.

[0036] In some embodiments of present invention, the compound of formula (I) for the claimed use has a heterocycloalkyl five- or six-membered ring containing one or more heteroatoms selected from N, O, and S.

[0037] In other embodiments of the invention the compound of formula (I) for the claimed has a heterocycloalkyl ring selected from the group consisting of tetrahydrofuran, pyrrolidine, or thiophene, piperidine, pyridine, or tetrahydrothiopyran, 1,4 dioxane, imidazole, pyrazole, pyrimidine, pyridazine, pyrazine, oxazole, thiazole, or morpholine.

[0038] In a further embodiment of the invention the compound of formula (I) for the claimed use has a substituted heterocycloalkyl ring.

[0039] In a most preferred embodiment of the invention the compound for the claimed use is selected from the group consisting of:

[0040] III IV

[0041]

[0042] 10 XIII XIV

[0043]

[0044] XXI XXII

[0045] Moreover, the present invention also discloses compounds of formula (I) or any pharmaceutical or acceptable salt, ester or solvate thereof:

[0046] (Formula I) selected from the group consisting of:

[0047] XIII XIV

[0048]

[0049] XXI XXII

[0050] The present invention also relates to pharmaceutical composition comprising at least one compound selected from the group consisting of compounds X-XXII. The aforesaid compositions can optionally comprise at least one inactive ingredient or excipient. Particularly those inactive ingredients or excipients can be selected from the group consisting of carriers, cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers and antioxidants. The invention also discloses the compounds X-XXII or the pharmaceutical compositions comprising the same, for use as a medicament (first medical use). Similarly, the present invention relates to compounds X-XXII for use in the treatment or prevention of diseases or conditions.

[0051] Finally, the invention also covers pharmaceutical compositions comprising at least one compound of formula (I) for use in the treatment or prevention of a disease or condition that benefits from the modulation and / or activation of the AMPK / Sirtl pathways, including chronic venous insufficiency, Raynaud’s phenomenon, peripheral microangiopathies, non-cancerous vascular malformations, ischemic limb diseases (acute peripheral arterial occlusion), osteoporosis, sarcopenia, fracture healing, osteoarthritis, vitiligo, rosacea, atopic dermatitis (eczema), melasma (hyperpigmentation or chloasma), skin aging, non-fibrotic chronic kidney disease such as Berger’s disease (IgA Nephropathy), glomerular disorders, renal tubular acidosis, mitochondrial myopathies, age-related macular degeneration (AMD), and rare vascular disorders frailty syndrome.

[0052] Particularly, the pharmaceutical compositions or compounds for use above mentioned, wherein the disease or condition is associated with vascular endothelial senescence. Additionally or alternatively, the diseases or conditions can be treated by the activation of AMP-activated protein kinase / Sirtuin 1 pathways.

[0053] The aforesaid pharmaceutical compositions for use, in an embodiment of the invention, further comprise at least one inactive ingredient or excipient selected from the group consisting of: carriers, cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers and antioxidants.

[0054] As shown in Figure 1 A, surprisingly, compound VII, as representative of the cannabinoid aminoquinone compounds disclosed herein, phosphorylates AMPK and identical results were obtained with the analogue compound XIII (Figure IB). Compounds VII (Fig. 2A) and XIII (Fig. 3A) also induces the expression of the nicotinamide adenine dinucleotide (NAD)-dependent protein Sirtl in endothelial cells. In addition, compound VII induces the expression and the expression of the nicotinamide phosphoribosyl transferase (NAMPT) (Figure 2A) and increased the Sirtl activity (Figure 2B) and NAD+ activity (Figure 2C). Similar results were observed with compound XIII (Fig. 3B and 3C). Moreover, compound VII prevented the inhibition of Sirtl induced by high concentration of glucose (80 mM) (Figure 2D). One of the consequences of the AMPK / Sirtl pathways activation is the induction of transcriptional activation of the hypoxia response element promoter HRE-Luc). Therefore, HRE-Luc activation can be used as surrogated marker of AMPK / Sirtl activation. As depicted in Figure 3 either dosomorphin (DS), an inhibitor of AMPK, or EX527, an inhibitor of Sirtl, inhibited compound VII and XHI-induced HRE- Luc activation (Figure 4A and 4B). All the 25 specific examples of the cannabinoid aminoquinone compounds of Formula I provided herein, including compounds la-IX, activated AMPK / Sirtl (Table 1 in Figure 16).

[0055] Figure 16 shows Table 1 in which NIH-3T3-HRE-luc cells were seeded in 96-well plates and incubated with the disclosed compounds. Luciferase activity was measured after 6 h of stimulation and the EC50 for each compound calculated.

[0056] Vascular endothelial cells were treated with H2O2 for 4 hours on days 2 and 5 of the experiment. The pre-treatment with compound VII for 1 h was able to reduce the SA-P- gal-stained cells (Figure 5A) and the expression of PAI-1 protein, a senescence marker, increased after H2O2 treatment at day 7 as compared with the control group (Figure 5B). In addition, Sirtl protein expression was reduced in senescent cells but was recovered with the treatment with compound VII (Figure 5B). Because each compound comprising Formula I, activates AMPK / Sirtl, the skilled artisan would expect any compound comprising Formula I to have the ability to prevent endothelial vascular senescence. Accordingly similar results were found with compound XIII (Fig. 6A and 6B).

[0057] It is well known that senescence is linked to cell death induced by external harmful stimuli including inflammation (Ota et al, 2010). Compound VII prevented cytotoxicity induced by the prooxidant H2O2, Oxo-LDL and high concentration of glucose (Figure 7A, Figure 7B, Figure 7C). Also, compound VII strongly inhibited the expression of the inflammatory marker VCAM-1 in EA.hy926 vascular endothelial cells stimulated with TNFoc plus IL-ip. Several cytoplasmic proteins have been described to associate with Tight Junction (TJ) transmembrane proteins and to contribute somehow to TJ integrity in senescent vascular endothelial cells. Among them, zonula occludens-1 (ZO-1) expression and distribution in endothelial cells is decisive in the process of formation of tight junctions between endothelial cells. ZO-1 forms heterodimers with ZO-2 and ZO-3 and interacts with claudins at TJs, then anchoring this multimolecular complex to the actin cytoskeleton. Compound VII clearly restored the reduced expression of ZO-1 and Claudin 1 (CLD1) in EA.hy926 vascular endothelial cells treated with the proinflammatory cytokines TNFa plus IL-6 (Figure 8).

[0058] In the vascular system, angiogenesis and arteriogenesis, although mediated by different physiological mechanisms, play a unique yet equally important role in both, health and disease. Arteriogenesis is the physiological pathway intrinsically related to endothelial vascular senescence. Angiogenesis, the formation of new blood vessels from a preexisting vascular bed, occurs naturally during wound healing. It plays a critical role in tissue growth and repair. Otherwise, the term arteriogenesis refers to anatomic transformation of preexisting arterioles with increasing lumen area and wall thickness, due to a thick muscular layer and purchasing of viscoelastic and vasomotor capacities. Arteriogenesis differs from angiogenesis in several aspects, the most important being the dependence of angiogenesis on hypoxia and the dependence of arteriogenesis on inflammation (Han & Kim, 2023; Potente et al., 2007; Zhang et al., 2017). Ischemic vascular endothelial inflammation and senescence was induced in mice by double ligation in the femoral arteria (CLI). The collateral vessels in the hind limb of the animals are shown 10 and 28 days after ischemia. Compound VII treatment clearly increased arteriogenesis in the ligated limb compared to the ligated limb without treatment. However, in the case of not ligated limb treated with compound VII, much less collateral formation was observed, in comparison with control limb (Figure 9A). Similar results were obtained in mice 28 days after ischemia (Figure 9B). Compound VII did not induce arteriogenesis in the nonischemic limbs, indicating that the effect of compound VII is specific for damaged tissues. Compound XIII treatment also increased arteriogenesis in the ligated limb compared to the ligated limb without treatment (Fig. 15). Micro-CT (pCT) showed that the ischemic limb treated with compound VII had higher densities of vessels (marked by arrows) than clamped limb without treatment in the 10 days after surgery (Figure 10A). Moreover, in high-resolution mCT images performed 28 days after femoral occlusion (Figure 10B), it is observed that the distribution of vessels in the mouse limbs was similar between the untreated (Control) and treated groups (C+ VII). The number of vessels were significantly reduced in the ligated limb (CLI) and fully restored after treatment with compound VII (CLI+VII). Immunohistochemistry analyses show that compound VII increases capillary density and enhances endothelial cells proliferation and induces angiogenic gene expression in the affected leg but not in the contralateral leg (Figure 11 A, Figure 11B). The antifibrotic effect of compound VII in ischemic tissue was evaluated by Tenascin-C (TNC) immunofluorescent staining, a tissue biomarker marker for fibrosis, 28 days after ischemia. The treatment with oral formulation of compound VII alleviated the deposition of TNC in ischemic muscles relative to non-treated ischemic muscle. No expression of TNC was found in the control mattes, with or without treatment (Figure 12A, Figure 12B). Moreover, the expression of Sirtl was clearly reduced in the ischemic limb and was completely restored by the treatment with compound VII (Figure 13 A, Figure 13B).

[0059] The aorta ring assay is a physiologically assay to measure arteriogenesis. The strength of the assay is the adjustment to diverse applications, such as testing of several molecules, including small drugs. In comparison with VEGF as a positive control, compounds XIII, XVI and XVIII significantly induced vascularization, indicated by the formation of new sprouts as well as sprout area (Figure 14A, Figure 14B, Figure 14C). In addition, compound XIII showed and enhancement in the vessel / area of the ischemic limb in the CLI murine model (Figure 15).

[0060] The determination of whether any specific compound comprising Formula I would have a benefit in the treatment and prevention of diseases associated with endothelial vascular senescence can be made by the skilled artisan without undue experimentation as also disclosed in the examples.

[0061] Especially, endothelial dysfunction, closely associated with endothelial (vascular) senescence, contributes to the pathogenesis of various age-related cardiovascular diseases, including vascular dementia, macular degeneration, renal failure, and critical limb ischemia (Han & Kim, 2023). Addressing endothelial senescence is therefore pivotal in managing these diseases. Thus, the compounds described herein may be used in the treatment of vascular dementia, (age related) macular degeneration, acute renal failure (acute kidney disease), and critical limb ischemia. The term critical limb ischemia as used herein refers to acute peripheral arterial occlusion. Thus, these terms may be used interchangeably herein.

[0062] AMPK and Sirtl activators have demonstrated therapeutic potential across a range of conditions. In metabolic disorders such as type 2 diabetes, obesity, and chronic venous insufficiency, these activators enhance glucose uptake, insulin sensitivity, and fatty acid oxidation while reducing lipid accumulation and inflammation (Ruderman et al., 2010; Guarente, 2013). In vascular conditions like Raynaud’s phenomenon, peripheral microangiopathies, vascular malformations (non-cancerous), and ischemic limb diseases (non-fibrotic and non-fibrotic), they improve endothelial nitric oxide production, enhance blood flow, and support angiogenesis (Ouchi et al., 2010). Thus, the compounds described herein may be used in the treatment of Raynaud’ s phenomenon, peripheral microangiopathies, vascular malformations (non-cancerous), and ischemic limb diseases (non-fibrotic and fibrotic).

[0063] Non-limiting examples of vascular malformations include cerebral arteriovenous malformations (AVMs), vascular lesions of the skin, spinal cord arteriovenous malformations (AVMs), hepatic arteriovenous (AV) malformation and / or capillary malformations.

[0064] Peripheral microangiopathies refer to diseases affecting the small blood vessels (microvasculature) in the periphery of the body, often leading to tissue ischemia, organ dysfunction, and systemic complications. These conditions are typically characterized by endothelial damage, microthrombosis, or abnormal vessel remodeling (Arnold et al., 2017)

[0065] Non limiting examples of peripheral microangiopathies are microangiopathic hemolytic anemia or diabetic microangiopathy, hypertensive microangiopathy, thrombotic microangiopathies, cryoglobulinemic vasculitis, small vessel vasculitis (e g., granulomatosis with polyangiitis, microscopic polyangiitis, IgA vasculitis). Diabetic microangiopathy, including retinopathy, is characterized by abnormal growth and leakage of small blood vessels, resulting in local edema and functional impairment of the affected tissues (Madonna et al, 2017). These activators also play a vital role in musculoskeletal and bone health by improving mitochondrial function and autophagy. They prevent sarcopenia, enhance fracture healing without scarring, and address bone metabolic disorders in general such as osteoporosis and Paget’s disease (Chen et al., 2014). By stimulating osteoblast activity and reducing oxidative stress, they promote bone remodeling and maintain muscle integrity by modulating protein turnover and mitochondrial health (Canto et al., 2012).

[0066] As used herein, the term bone metabolic disorder relates to osteoporosis, osteopenia, osteomalacia (adults) and rickets (children), osteitis fibrosa cystica and / or Paget's disease of bone.

[0067] Therefore, the compounds described herein may be used in the treatment of bone metabolic disorders such as osteoporosis, osteopenia, osteomalacia (adults) and rickets (children), osteitis fibrosa cystica and / or Paget's disease of bone. The compounds described herein may additionally or alternatively be used in the treatment of sarcopenia and / or to enhance fracture healing without scarring.

[0068] Recent studies have found that abnormal AMPK / SIRT1 activity is linked to the development of osteoarthritis and AMPK serves as a potent activator of autophagy to protect chondrocytes from cellular stress. Moreover, the AMPK / SIRT1 pathway is known to be associated with autophagy and may be a potential pharmacological target for osteoarthritis (Loeser et al., 2016) (Zhou at el., 2017).

[0069] Therefore, the compounds described herein may be used could for treating osteoarthritis or other cartilage-related diseases.

[0070] In dermatology, AMPK and Sirtl activators have potential applications for treating vitiligo, rosacea, atopic dermatitis, melasma, and skin aging. By reducing oxidative stress and inflammation, these compounds support melanocyte function, improve skin barrier integrity, and counteract cellular aging processes (Houtkooper et al., 2012). Their ability to stimulate mitochondrial biogenesis further enhances their anti-aging effects on the skin (Haigis & Sinclair, 2010). Thus, the compounds described herein may be used in the treatment of vitiligo, rosacea, atopic dermatitis, melasma, and skin aging. The term skin aging includes inter alia photoaging, actinic keratoses and skin cancers.

[0071] The term melasma is interchangeably used with the terms hyperpigmentation and chloasma herein.

[0072] Renal health also benefits from AMPK and Sirtl activation, with therapeutic potential in conditions such as chronic kidney disease (non-fibrotic and fibrotic), acute kidney disease, glomerular disorders (non-immune related), renal tubular acidosis (Mehta et al., 2014). These compounds improve mitochondrial function, reduce oxidative stress, and suppress inflammation, protecting renal cells and promoting repair. Thus, the compounds described herein may be used in the treatment of chronic kidney disease (non-fibrotic and fibrotic), acute kidney injury (kidney ischemia-reperfusion injury), glomerular disorders (non-immune), and renal tubular acidosis.

[0073] Non-limiting examples of glomerular disorders include nephrotic syndrome, nephritic syndrome, fibrillary and immunotactoid glomerulopathies, membranoproliferative glomerulonephritis (GN), and lupus nephritis.

[0074] Neurological disorders also stand to benefit from AMPK and Sirtl activators. By promoting mitochondrial biogenesis, reducing oxidative stress, and enhancing autophagy, they mitigate neuronal damage and improve synaptic plasticity. This makes them promising candidates for treating mitochondrial myopathies, and age-related macular degeneration (Kim et al., 2011). Thus, the compounds herein may be used in the treatment of mitochondrial myopathies, and age-related macular degeneration.

[0075] Non-limiting examples of mitochondrial myopathies are Kearns-Sayre syndrome (KSS), Leigh syndrome (subacute necrotizing encephalomyopathy) and maternally inherited Leigh syndrome (MILS), Mitochondrial DNA depletion syndrome (MDS), Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Maternally inherited deafness and diabetes (MIDD), Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), Myoclonus epilepsy with ragged red fibers (MERRF), Neuropathy, ataxia, and retinitis pigmentosa (NARP) and / or Pearson syndrome. In rare diseases, including inherited metabolic and vascular AMPK and Sirtl activators regulate disrupted metabolic and energy pathways, offering a novel therapeutic approach. They address cellular dysfunction caused by oxidative stress, inflammation, and impaired autophagy, thus improving outcomes for these challenging conditions (Finkel et al., 2009; Verdin et al., 2015). For example, AMPK activators such as AICAR and Sirtl activators like resveratrol have shown promise in mitigating symptoms in rare mitochondrial disorders (Houtkooper et al., 2012). Additionally, studies indicate these activators can modulate the progression of rare vascular diseases such as hereditary hemorrhagic telangiectasia by improving endothelial function (Shen et al., 2020). Thus, the compounds disclosed herein can be used in the treatment of inherited metabolic and vascular disorders.

[0076] Non limiting examples of inherited metabolic disorders include Leigh Syndrome, MELAS, Pompe Disease, Gaucher Disease, Fabry Disease, Carnitine Palmitoyltransferase II Deficiency, Propionic Acidemia.

[0077] Examples of inherited vascular disorders as used herein include Ehlers-Danlos Syndrome (Vascular Type), Hereditary Hemorrhagic Telangiectasia (HHT), Marfan Syndrome, Loeys-Dietz Syndrome, Familial Hypercholesterolemia, CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), Fabry Disease, Alpha-1 Antitrypsin Deficiency (vascular complications), Pseudoexfoliation Syndrome (vascular-related glaucoma), and Homocystinuria (vascular complications).

[0078] Non-limiting examples of rare non-inherited vascular disease are Takayasu Arteritis, Buerger’s Disease (Thromboangiitis Obliterans), Hypersensitivity Vasculitis, Kounis Syndrome (Coronary Allergy Syndrome), Acquired Ehlers-Danlos Syndrome (autoantibody -related), Migratory Thrombophlebitis (Trousseau’s Syndrome), Secondary Raynaud’s Syndrome (associated with other conditions), Acquired Fibromuscular Arterial Stenosis, Superior Vena Cava Syndrome, Non-congenital Fibromuscular Dysplasia, Secondary Cerebral Vasospasm Syndrome, Mondor’s Syndrome (Superficial Thrombophlebitis), Leriche Syndrome (aortoiliac occlusion), Idiopathic Cutaneous Vasculitis Syndrome, and Vasculitis Associated with Viral Infections (e.g., hepatitis or HIV). AMPK and Sirtl activators have shown promise in addressing age-related diseases, including frailty syndrome, osteoporosis, sarcopenia, cognitive decline, and skin aging. By mimicking the effects of caloric restriction, they enhance mitochondrial efficiency and promote cellular repair processes, improving resilience to age-related degeneration (Lopez-Otin et al., 2013). Thus, the compounds as disclosed herein can be used in the treatment of frailty syndrome, osteoporosis, sarcopenia, cognitive decline, and skin aging.

[0079] The term frailty syndrome as used herein refers to a common clinical syndrome in older adults that carries an increased risk for poor health outcomes including falls, incident disability, hospitalization, and mortality (Quian-Li Xue, 2011).

[0080] Non limiting examples of rare vascular disorders include Takayasu Arteritis, Behcet's Disease, Fibromuscular Dysplasia (FMD), Hereditary Hemorrhagic Telangiectasia (HHT), Ehlers-Danlos Syndrome (Vascular Type), Moyamoya Disease and / or Klippel- Trenaunay Syndrome (Sun et al., 2021) (Naganathan et al., 2023).

[0081] That AMPK and Sirtl activators have an effect as pharmacologic compounds is further proven by the use of AMPK and Sirtl activators as pharmacological agents, natural compounds, NAD+ precursors, and lifestyle interventions. Metformin, a widely used AMPK activator, provides anti-aging and cardiovascular benefits (Rena et al., 2017). Natural compounds like resveratrol, a polyphenol that activates Sirtl and indirectly stimulates AMPK, improve metabolic and cardiovascular health (Baur et al., 2006). Berberine, another AMPK activator, enhances glucose metabolism and lipid profiles, while flavonoids like quercetin and pterostilbene reduce inflammation and oxidative stress through AMPK / Sirtl activation (Xu et al., 2021). NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) boost NAD+ levels, activating Sirtl with downstream effects on AMPK (Yoshino et al., 2018). Lifestyle interventions like caloric restriction and intermittent fasting activate both pathways by increasing NAD+ and improving cellular stress resilience, while exercise directly stimulates AMPK, enhancing mitochondrial function and overall metabolic health (Evans et al., 2004).

[0082] Preclinical studies of cannabinoid-derived aminoquinone compounds highlight their efficacy in models of scleroderma (Garcia-Martin et al., 2019), multiple sclerosis (Navarrete et al, 2020), and traumatic brain injury (Navarrete et al, 2022), though their effects on the AMPK / Sirtl pathway are newly disclosed in the present invention.

[0083] In summary, AMPK and Sirtl activators represent a promising therapeutic strategy for a wide range of chronic and age-related diseases. These activators offer innovative solutions for diseases and indications such as chronic venous insufficiency, Raynaud’s syndrome, peripheral microangiopathies, non-cancerous vascular malformations, acute peripheral arterial occlusion, metabolic bone disorders, sarcopenia, fracture healing, osteoarthritis, vitiligo, rosacea, atopic dermatitis, melasma, skin aging, non-fibrotic chronic kidney disease, glomerular disorders, renal tubular acidosis, mitochondrial myopathies, age-related macular degeneration, rare vascular disorders, frailty syndrome, inherited metabolic and vascular disorders. Compounds X-XII as disclosed herein may further be used in the treatment and prevention of acute kidney disease, chronic kidney disease (fibrotic), vascular dementia, type 2 diabetes, obesity, and / or traumatic brain injury.

[0084] As used herein the activation of the AMP-activated protein kinase (AMPK)ZSirtuin 1 (Sirtl) pathways is an activation of the AMP-activated protein kinase (AMPK) / Sirtuin 1 (Sirtl) pathway compared to the activity of the AMP-activated protein kinase (AMPK) / Sirtuin 1 (Sirtl) pathway before or without the application of one or more compounds disclosed herein. The skilled person knows how to measure the activation of the AMP-activated protein kinase (AMPK) / Sirtuin 1 (Sirtl) pathway. For example, the skilled person can perform the experiments as disclosed herein in the examples to analyze the activation of the AMP-activated protein kinase (AMPK) / Sirtuin 1 (Sirtl) pathway.

[0085] Also provided herewith is a method of treating or preventing vascular diseases associated with vascular endothelial senescence.

[0086] As used herein, the term vascular diseases associated with vascular endothelial senescence refers to any disease as described herein that is associated with vasculature, such as chronic venous insufficiency, Raynaud’s syndrome, peripheral microangiopathies, non-cancerous vascular malformations, acute peripheral arterial occlusion, rare vascular disorders, inherited vascular disorders and / or vascular dementia. The use of the compounds disclosed herein comprises a use of the compounds in a method of treatment or prevention of any one of the diseases mentioned herein wherein the method may comprise administering to the mammal a compound comprising Formula I in a manner sufficiently effective to prevent and / or to treat any one of the diseases mentioned herein or vascular diseases associated with vascular endothelial senescence.

[0087] The compound of formula I is

[0088] (Formula 1) wherein

[0089] R1is a Ci-C6unbranched or branched alkyl that is optionally substituted at its terminus with a group selected from a 5- or 6-membered heterocycloalkyl, a phenyl, an amino group, NH(CO)CH3, OH, or C1-C3 alkoxy, wherein the 5- or 6-membered heterocycloalkyl can be optionally substituted with C1-C4 alkyl, and

[0090] R2is CH3or CH2CH2CH3

[0091] In some embodiments the heterocycloalkyl is a five- or six-membered ring containing one or more heteroatoms selected from N, O, and S. In some embodiments the heterocycloalkyl may be optionally substituted. In some embodiments the heterocycloalkyl is tetrahydrofuran, pyrrolidine, or thiophene. In other embodiments the heterocycloalkyl is piperidine, pyridine, or tetrahydrothiopyran. In yet other embodiments the heterocycloalkyl is 1,4 dioxane, imidazole, pyrazole, pyrimidine, pyridazine, pyrazine, oxazole, thiazole, or morpholine.

[0092] As discussed above, any compound comprising Formula I is expected to prevent or to revert vascular endothelial cells senescence; the determination of whether, and to what degree, any compound comprising Formula I inhibits or prevents vascular endothelial cells senescence can be determined by the skilled artisan without undue experimentation, for example by using the methods described in Examples 3 to 14.

[0093] In some of the embodiments of the present invention, R2is CH3. In additional embodiments, the compound consists in any one of Compounds la-XXII.

[0094] In further embodiments, the mammal is administered the compound parenterally, enterally, transmucosally, or transdermally.

[0095] In these embodiments, the compound can be administered by any route, e.g., parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), enteral (oral), transmucosal (nasal, vaginal, rectal, or sublingual), or transdermal (e.g., through a patch), as described above.

[0096] In yet another embodiment, present invention discloses cannabinoid aminoquinone compounds of formula I selected from:

[0097]

[0098] Another embodiment of the present invention relates to the above-mentioned compounds comprising Formula I, selected from the group of compounds X to XXII for use as a medicament.

[0099] Some embodiments of the present disclosure relate to the use of the above-mentioned compounds comprising Formula I formulated in compositions, including pharmaceutical compositions, that comprise at least one of the compounds of the disclosure in a pharmaceutically acceptable excipient. In some of these embodiments, the compound is suitable for administration to a patient by any route which effectively transports the compound of interest to the appropriate or desired site of action, such as oral, nasal, topical, pulmonary, transdermal or parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.

[0100] In some of these embodiments, the compound is combined with at least another active compound, e g., another compound effective in reducing or preventing vascular endothelial senescence such as resveratrol, polyphenols metformin and rapamycin. Alternatively, or additionally, the compositions can be formulated with at least one inert ingredient as a carrier or excipient such as: cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers and antioxidants. Any pharmacologically acceptable buffer may be used, e.g., TRIS or phosphate buffers.

[0101] As used herein, “active compound or active principle” refers to a chemical entity which exerts therapeutic effects when administered to human or animal beings.

[0102] Typical compositions include the compounds described herein, or derivatives thereof, associated with pharmaceutically acceptable excipients, which may be a carrier or a diluent, as a way of example. Such compositions can be in the form of a capsule, sachet, stick pack, paper or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the compound of interest can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier that may be in the form of an ampoule, capsule, sachet, stick pack, paper, or another container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The compound of interest can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The formulations may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.

[0103] The pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and / or coloring substances and the like, which do not deleteriously react with the active compounds.

[0104] To prepare topical formulations, the compound of interest is placed in a dermatological vehicle as is known in the art. The amount of the compound of interest to be administered and the compound's concentration in the topical formulations depend upon the vehicle, delivery system or device selected, the clinical condition of the patient, the side effects and the stability of the compound in the formulation. Thus, the physician employs the appropriate preparation containing the appropriate concentration of the compound of interest and selects the amount of formulation administered, depending upon clinical experience with the patient in question or with similar patients.

[0105] For oral administration, either solid or fluid unit dosage forms can be prepared. For preparing solid compositions such as tablets, the compound of interest is mixed into formulations with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers.

[0106] Capsules are prepared by mixing the compound of interest with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size. Soft gelatin capsules are prepared by machine encapsulation of slurry of the compound of interest with an acceptable vegetable oil, light liquid petrolatum or other inert oil. Fluid unit dosage forms for oral administration such as syrups, elixirs and suspensions can be prepared. The water-soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form syrup. An elixir is prepared by using a hydroalcoholic (e.g., ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent. Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like. Appropriate formulations for parenteral use are apparent to the practitioner of ordinary skill, such as the use of suitable injectable solutions or suspensions. The formulation, which is sterile, is suitable for various topical or parenteral routes including intradermal, intramuscular, intravascular, and subcutaneous.

[0107] In addition to the compound of interest, the compositions may include, depending on the formulation and mode of delivery desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which include vehicles commonly used to form pharmaceutical compositions for animal or human administration. The diluent is selected so as not to unduly affect the biological activity of the combination.

[0108] Examples of such diluents that are especially useful for injectable formulations are water, the various saline, organic or inorganic salt solutions, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may include additives such as other carriers; adjuvants; or non-toxic, non-therapeutic, non- immunogenic stabilizers and the like.

[0109] Furthermore, excipients can be included in the formulation. Examples include cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers and antioxidants. Any pharmacologically acceptable buffer may be used, e.g., TRIS or phosphate buffers. Effective amounts of diluents, additives, and excipients are those amounts that are effective to obtain a pharmaceutically acceptable formulation in terms of solubility, biological activity, etc.

[0110] The compound of interest may be incorporated into a microsphere. The compound of interest can be loaded into albumin microspheres, from which it is possible to recover such microspheres in a dry powder for nasal administration. Other materials suitable for the preparation of microspheres include agar, alginate, chitosan, starch, hydroxyethyl starch, albumin, agarose, dextran, hyaluronic acid, gelatin, collagen, and casein. The microspheres can be produced by various processes known to the person skilled in the art such as a spray drying process or an emulsification process.

[0111] For example, albumin microspheres can be prepared by adding rabbit serum albumin in phosphate buffer to olive oil with stirring to produce water in oil emulsion. Glutaraldehyde solution is then added to the emulsion and the emulsion stirred to crosslink the albumin. The microspheres can then be isolated by centrifugation, the oil removed, and the spheres washed, e.g., with petroleum ether followed by ethanol. Finally, the microspheres can be sieved and collected and dried by filtration.

[0112] Starch microspheres can be prepared by adding a warm aqueous starch solution, e.g., of potato starch, to a heated solution of polyethylene glycol in water with stirring to form an emulsion. When the two-phase system has formed (with the starch solution as the inner phase) the mixture is then cooled to room temperature under continued stirring whereupon the inner phase is converted into gel particles. These particles are then filtered off at room temperature and slurred in a solvent such as ethanol, after which the particles are again filtered off and laid to dry in air. The microspheres can be hardened by well- known cross-linking procedures such as heat treatment or by using chemical cross-linking agents. Suitable agents include dialdehydes, including glyoxal, malondialdehyde, succinicaldehyde, adipaldehyde, glutaraldehyde and phthalaldehyde, diketones such as butadione, epichlorohydrin, polyphosphate, and borate. Dialdehydes are used to crosslink proteins such as albumin by interaction with amino groups, and diketones form schiff bases with amino groups. Epichlorohydrin activates compounds with nucleophiles such as amino or hydroxyl to an epoxide derivative.

[0113] Another embodiment of the disclosure is the dosage scheme. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for subjects, e.g., mammalian subjects, e.g., humans, dogs, cats, and rodents, each unit containing a predetermined quantity of active material calculated to produce the desired pharmaceutical effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the unit dosage forms of this disclosure are dictated by and dependent on (a) the unique characteristics of the active material and the effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for use in humans and animals. Examples of unit dosage forms are tablets, capsules, pills, powder packets, wafers, suppositories, granules, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampoules, vials, aerosols with metered discharges, segregated multiples of any of the foregoing, and other forms as herein described. The compositions can be included in kits, which can contain one or more unit dosage forms of the composition and instructions for use to treat one or more of the disorders described herein. Slow or extended-release delivery systems, including any of a number of biopolymers (biological-based systems), systems employing liposomes, colloids, resins, and other polymeric delivery systems or compartmentalized reservoirs, can be utilized with the compositions described herein to provide a continuous or long-term source of therapeutic compound. Such slow-release systems are applicable to formulations for delivery via topical, intraocular, oral, and parenteral routes.

[0114] An effective amount of the compound of interest is employed in treatment. The dosage of compounds used in accordance with the disclosure varies depending on the compound and the condition being treated for example the age, weight, and clinical condition of the recipient patient. Other factors include: the route of administration, the patient, the patient's medical history, the severity of the disease process, and the potency of the particular compound. The dose should be sufficient to ameliorate symptoms or signs of the disease treated without producing unacceptable toxicity to the patient. In general, an effective amount of the compound is that which provides either subjective relief of symptoms or an objectively identifiable improvement as noted by the clinician or other qualified observer. The skilled artisan can determine an appropriate dosage for any particular use of route of administration without undue experimentation.

[0115] The term “comprise”, “comprising” and their variants, throughout the description and the claims, includes, specifically, the term “consisting” or “consisting of’.

[0116] BRIEF DESCRIPTION OF DRAWINGS

[0117] The figures of the invention are briefly described below. An in deep explanation of each figure is included in every pertinent example.

[0118] Figure 1. Compound VII induces phosphorylation of AMPK. HEK-293T cells (A) and EA.hy926 cells (B) were preincubated with DS for 30 minutes and then, stimulated for 3 hours with either compound VII (A) or compound XIII (B). The expression of pAMPK and AMPK total was detected by western blot. Actin was detected as a loading control. Figure 2. Effect of compound VII on Sirtl expression and NAD+ / NADPH ratio. (A) HEK-293T cells were stimulated with the indicated concentrations of compound VII for 3 hours. The expression of Sirtl and Visfatin (NAMPT) was detected by western blot. Actin was detected as a loading control. (B) Sirtl activity for compound VII was determined with the Sirtl Activity Assay Kit (Fluorometric). Srtl720 was used as a positive control. Data represent the mean ± SD (n = 3). (C) NAD+ / NADH ratio was determined in EA.hy296 with the NAD+ / NADH assay kit (Colorimetric). Data represent the mean ± SD (n = 3), and significance was determined by one-way ANOVA followed by Dunnett test. **p<0.01 Control vs compound VII treated cells. (D) EA.hy926 cells were pre-stimulated with compound VII during Ih. Then, cells were exposed to supplemental D-glucose for 24h. The expression of Sirtl was detected by western blot and actin was detected as a loading control.

[0119] Figure 3. Effect of compound XIII on Sirtl expression and NAD+ / NADPH ratio. (A) EA.hy926 cells were stimulated with the indicated concentrations of compound XIII for 3 hours. The expression of Sirtl was detected by western blot. Actin was detected as a loading control. (B) Sirtl activity for compound XIII was determined with the Sirtl Activity Assay Kit (Fluorometric). Srtl720 was used as a positive control. Data represent the mean ± SD (n = 3). (C) NAD+ / NADH ratio was determined in EA.hy296 with the NAD+ / NADH assay kit (Colorimetric). Data represent the mean ± SD (n = 3), and significance was determined by one-way ANOVA followed by Dunnett test. **p<0.01 Control vs compound XIII treated cells. (D) EA.hy926 cells were pre-stimulated with compound XIII during Ih. Then, cells were exposed to supplemental D-glucose for 24h. The expression of Sirtl was detected by western blot and actin was detected as a loading control.

[0120] Figure 4. HRE-Luc induction stimulated by either compound VII or XIII is impaired after AMPK and Sirtl inhibitors treatment. HRE-luc induction was determined after 6 h of compound VII (A) or compound XIII (B) treatment with or without AMPK (DS) and Sirtuin 1 inhibitors (EX527) in NIH-3T3 -HRE-luc cells. Inhibitors were added 30 min before the compounds VII or XIII. Data represent the mean ± SD (n =2-8) and significance was determined by one-way ANOVA followed by Tukey s test. ****p<0.001, compounds + inhibitors vs compounds. Figure 5. Compound VII inhibits HiCh-induced senescence in vascular endothelial cells. (A) SA-P-gal staining in HMEC-1 cells after the treatment with H2O2 to the induction of senescence and compound VII at different doses. Data represent the mean ± SD (n =2-8) and significance was determined by one-way ANOVA followed by Dunnett test. ****p<0.001, H2O2 vs Control; ****p<0.001, compound VII + H2O2 vs H2O2. (B) Sirtl and PAI-1 protein levels after the treatment with H2O2 and compound VII in HMEC- 1 cells. Tubulin was detected as a loading control.

[0121] Figure 6. Compound XIII inhibits HzCh-induced senescence in vascular endothelial cells. (A) SA-P-gal staining in HMEC-1 cells after the treatment with H2O2 to the induction of senescence and compound XIII at different doses. Data represent the mean ± SD (n =2-8) and significance was determined by one-way ANOVA followed by Dunnett test. ****p<0.001, H2O2 vs Control; ****p<0.001, compound XIII + H2O2 vs H2O2. (B) Sirtl and p21 protein levels after the treatment with H2O2 and compound VII in HMEC-1 cells. Actin was detected as a loading control.

[0122] Figure 7. Compound VII protects endothelial vascular cells against exogenous damage. EA.hy926 cells were pre-stimulated with compound VII during Ih. Then, cells were exposed to supplemental H2O2 (A), oxo-LDL Glucose (B) or high concentration glucose (C). Cell viability was calculated by MTT assay. Data represent the mean ± SD (n = 3). Data represent the mean ± SD (n=3), and significance was determined by oneway ANOVA followed by Tukey's test. ****p<0.0001; ***p<0.001; **p<0.01; *p<0.05.

[0123] Figure 8. Compound VII inhibits VCAM-1 expression and prevents the loss of ZO- 1 and CLD1 expression induced by proinflammatory cytokines TNFa and IL-ip Representative images of immunostaining of VCAM-1, ZO-1 and CLD1 in cultured EA.hy926 cells (A) and their quantification (B, C and D). Cells were counterstained with DAPI to identify nuclei. Data represent the mean ± SEM, and significance was determined by one-way ANOVA followed by Tukey s test. ****p<0.0001; ***p<0.001; **p<0.01; *p<0.05.

[0124] Figure 9. Compound VII enhances arteriogenesis in a Critical Limb Ischemia mouse model. Representative whole-mount images of Microfil vascular cast limbs at (A) 10 days and (B) 28 days. Collateral artery growth is indicated by arrows. Figure 10. Compound VII treatment augments arterial vascular growth in the Hind limb evaluated by 3D quantification of postischemic. Representative images of micro- CT analysis of arterial vasculature. (A) Micro-CT reconstruction of mouse hindlimb 10 days after femoral artery ligation. Yellow arrows indicated arterial vasculature. (B) Micro- CT reconstruction and segmentation mouse hindlimb at 28 days after surgery.

[0125] Figure 11. Compound VII treatment augments endothelial cell proliferation in the ischemic limb. Representative images of immunostaining of CD31 and Ki67 expression in gastrocnemius muscle of CLI mice (n=3-4 mice per group) (A) and their quantification (B). Data represent the mean ± SEM, significance was determined by one-way ANOVA followed by Tukey's test or one-way ANOVA non-parametric followed by a Kruskal- Wallis test. ****p<0.0001.

[0126] Figure 12. Compound VII treatment reduces fibrosis in a Critical Limb Ischemia mouse model. Representative images of immunostaining of TNC expression in gastrocnemius muscle of CLI mice (n=3-4 mice per group) (A) and their quantification

[0127] (B). Data represent the mean ± SEM, and significance was determined by one-way ANOVA non-parametric followed by a Kruskal-Wallis test. ***p<0.001.

[0128] Figure 13. Compound VII treatment restored the expression of Sirtl in the ischemic limb. Representative images of immunostaining of Sirtl expression in vessels of the gastrocnemius muscle of CLI mice (n=3-4 mice per group) (A) and its quantification (B). Data represent the mean ± SEM, and significance was determined by one-way ANOVA non-parametric followed by a Kruskal-Wallis test. **p<0.01.

[0129] Figure 14. Cannabidiol aminoquinone compounds (XIII, XVI and XVIII) induce neo-vasculogenesis in a ring aorta assay. Representative images of aortic ring assay for cannabidiol aminoquinone compounds XIII, XVI and XVIII (B) and their quantification

[0130] (C). Arrows indicate sprouts and sprouting area is delimited.

[0131] Figure 15. Compound XIII enhances arteriogenesis in a Critical Limb Ischemia mouse model. Representative whole-mount images of Microfil vascular cast limbs at 28 days. Collateral artery growth is indicated by arrows. Figure 16. Table 1 in which NIH-3T3-HRE-luc cells were seeded in 96-well plates and incubated with the disclosed compounds. Luciferase activity was measured after 6 h of stimulation and the EC50 for each compound calculated.

[0132] DESCRIPTION OF EMBODIMENTS

[0133] The examples of the present invention described below aim to illustrate its preferred embodiments without limiting its scope of protection.

[0134] Example 1. Synthesis of cannabidiol (CBD) aminoquinone derivatives

[0135] The route of synthesis is showed in Scheme 1. CBD was oxidized to quinone with SIBX to prepare VCE-004. The quinone intermediate was purified by chromatography to make the purification of the final products easier.

[0136] CBD VCE-004

[0137] Scheme 1

[0138] General procedure for the preparation of the target compounds

[0139] To a solution of the selected quinone (200 mg) in ethyl acetate (EtOAc) (5 mL) was added the amine (5-10 mol / mol) and the dark purple solution formed was stirred at room temperature in a system open to the air. The reaction mixture was washed with HC1 10%, dried (Na2SC>4) and concentrated to obtain a crude residue which was purified in the indicated conditions.

[0140] Synthesis of compounds la to IX was disclosed in the document US9701618.

[0141] In one embodiment, the cannabidiol derivative synthetized is selected from the group consisting of:

[0142] (rR,6'R)-3-(Ethylamine)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)[l,r- bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione,

[0143] (lR,6R)-3-(Pentylamine)-6-Hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)- [ 1 , 1'bi (cy cl ohexane)] -2' , 3 , 6 -tri ene-2, 5 -di one,

[0144] (rR,6'R)-3-(Isobutylamine)-6-Hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)[l,r- bi(cyclohexane)]-2', 3, 6-tri ene-2, 5-dione,

[0145]

[0146] (rR,6'R)-3-(Butylamine)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)[l,r- bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione,

[0147] (l'R,6'R)-3-(Methylamine)-6-Hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)[l,r- bi (cy c 1 ohexane)] -2' , 3 , 6 -tri ene-2, 5 -di one,

[0148]

[0149] (rR,6'R)-3-(Isopropylamine)-6-Hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)-[l,r- bi (eye 1 ohexane)] -2' , 3 , 6 -tri ene-2, 5 -di one,

[0150] ( I 'R,6'R)-3-(Benzylamine)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-l -en-2-yl)[ l , 1 '- bi (cy c 1 ohexane)] -2' , 3 , 6 -tri ene-2, 5 -di one,

[0151] (rR,6'R)-3-(Neopentylamine)-6-hydroxy-3'-methyl-)-4-pentyl-6'-(prop-l-en-2yl)-[l,rbi(cycl ohexane)]-2', 3, 6-triene-2, 5-dione, and

[0152]

[0153] (TR,6'R)3-(Isopentylamine)-6-Hydroxy-amine-3'-methyl-4-pentyl-6' -(prop-l-en-2-yl)- [1, l'-bi(cycl ohexane)]-2', 3, 6-triene-2, 5-dione.

[0154] For the synthesis of the cannabinoid aminoquinone compounds (X-XII) of present invention, to a solution of the quinone VCE-004 (200 mg, 0.61 mmol) in EtOAc (5 mL) was added 2-morpholinoethan-l -amine (0.79 mL, 6.10 mmol) and the dark purple solution formed was stirred for 2 h at room temperature in a system open to the air. The reaction mixture was concentrated to obtain a crude residue. The crude was purified by chromatography (SiCL, 30-50% EtOAc / hexanes) to obtain a dark oil (120 mg)

[0155] (17?,6'A)-6-hydroxy-3'-methyl-3-((2-morpholinoethyl)amino)-4-pentyl-6'-(prop-l-en- 2-yl)-[l, l'-bi(cycl °hexane)]-2', 3, 6-triene-2, 5-dione

[0156] To a solution of the quinone VCE-004 (200 mg, 0.61 mmol) in EtOAc (5 mL) was added A, / V-dimethylethane-l,2-diamine (0.66 mL, 6.10 mmol) and the dark purple solution formed was stirred overnight at room temperature in a system open to the air. The reaction mixture was concentrated to obtain a crude residue. The crude was purified by chromatography (SiO2, 40-60% EtOAc / hexanes) to obtain a dark oil (136 mg).

[0157] (17?,67?)-3-((2-(dimethylamino)ethyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop- l-en-2-yl)-[l,l'-bi(cyclohexane)]-2',3,6-triene-2,5-dione

[0158] To a solution of the quinone VCE-004 (200 mg, 0.61 mmol) in EtOAc (5 mL) was added A, A-dimethylpropane- 1,3 -diamine (0.76 mL, 6.10 mmol) and the dark purple solution formed was stirred overnight for 19 h at room temperature in a system open to the air. The reaction mixture was concentrated to obtain a crude residue. The crude was purified by chromatography (SiCh, 50-100% EtOAc / hexanes, 10% MeOH / EtOAc) to obtain a dark oil (172 mg, 66%). EtOAc was removed after crystallization in MeOH / water 8:2 to obtain a reddish solid (95 mg). (17?,67?)-3-((3-(dimethylamino)propyl)amino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop- l-en-2-yl)-[l,T-bi(cyclohexane)]-2',3,6-triene-2,5-dione

[0159] To a solution of the quinone VCE-004 (200 mg, 0.61 mmol) in EtOAc (5 mL) was added (l-methylpiperidin-4-yl)methenamine (0.39 mg, 3.05 mmol) and the dark purple solution formed was stirred for 19 h at room temperature in a system open to the air. The reaction mixture was concentrated to obtain a crude residue. The crude was purified by reverse phase chromatography (C18, 60-100% CH3CN / H2O) to obtain a reddish solid (224 mg)

[0160] (rA,6'A)-6-hydroxy-3'-methyl-3-(((l-methylpiperidin-4-yl)methyl)amino)-4-pen-tyl- 6'-(prop-l -en-2-yl)-[l,l'-bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione

[0161] To a solution of the quinone VCE-004 (200 mg, 0.61 mmol) in EtOAc (5 mL) was added .V-(2-ami noethyl) acetamide (0.29 mL, 3.05 mmol) and the dark purple solution formed was stirred overnight at room temperature in a system open to the air. Solvent was removed and CH2CI2 (7 mL) was added to obtain a solution, which was washed with HC1 10% (8 mL). The organic layer was dried (ISfeSCU) and concentrated to obtain a crude residue. The crude was purified by reverse phase chromatography (C18, 60-100% CH3CN / H2O) to obtain a dark solid (150 mg).

[0162] JV-(2-(((1R ,67R)-6-hydroxy-3'-methyl-2,5-dioxo-4-pentyl-6'-(prop-l-en-2-yl)-[l,- l'-bi(cyclohexane)]-2',3,6-trien-3-yl)amino)ethyl)acetamide

[0163] To a solution of the quinone VCE-004 (200 mg, 0.61 mmol) in EtOAc (5 mL) was added 2-aminoethan-l-ol (0.37 mL, 6.10 mmol) and the dark purple solution formed was stirred for 6 h at room temperature in a system open to the air. The reaction mixture was washed with HC1 10% (30 mL), dried (Na2SO4) and concentrated to obtain a crude residue. The crude was purified by reverse phase chromatography (C18, 60-100% CH3CN / H2O) to obtain a dark oil (138 mg)

[0164] (1 R, 67R)-6-hydroxy-3 -((2 -hydroxy ethyl) amino)-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)- [l,l'-bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione

[0165] To a solution of the quinone VCE-004 (200 mg, 0.61 mmol) in EtOAc (5 mL) was added 2-m ethoxy ethan-1 -amine (0.81 mL, 6.10 mmol) and the dark purple solution formed was stirred overnight at room temperature in a system open to the air. The reaction mixture was washed with HC1 10% (5 mL), dried (ISfeSCU) and concentrated to obtain a crude residue. The crude was purified by reverse phase chromatography (C18, 60-100% CH3CN / H2O) to obtain a dark oil (139 mg).

[0166] (1R ,6'R)-6-hydroxy-3-((2-methoxyethyl)amino)-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)- [l,l'-bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione

[0167] Example 2. Synthesis of cannabidivarin (CBDV) aminoquinone derivatives

[0168] These cannabidivarin aminoquinone derivatives are also represented by Formula I, wherein R2is always CH3. The route of synthesis is shown in Scheme 2. A solution of CBDV in di chloromethane was treated with manganese (Ill)-acetate (1 molar equivalent) and then with the amine (5 molar equivalents), and stirred in the dark at room temperature for the time indicated. The reaction was worked up by dilution with 2N H2SO4 and extraction with ethyl acetate. Removal of the solvent gave the crude aminoquinone, purified according to the indicated conditions.

[0169] Scheme 2

[0170] A stirred solution of cannabidivarin (CBDV) (200 mg, 0.70 mmol) in dichloromethane (5 mL) was treated with manganese (Ill)-acetate (162 mg, 0.70 mmol, 1 molar equivalent), and then isobutylamine (345 uL, 5 molar equivalents) was added dropwise. The reaction was stirred in the dark at room temperature for 6 days, and then worked up by dilution with 2N H2SO4 and extraction with ethyl acetate. Removal of the solvent gave the crude aminoquinone, purified by filtration on silica gel to obtain a dark powder (152 mg).

[0171] ((TR,6'R)-3-(3-methylpropylamino)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)-

[0172] [1,1' bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione)

[0173] A stirred solution of CBDV (200 mg, 0.70 mmol) in di chloromethane (5 mL) was treated with manganese (Ill)-acetate (162 mg, 0.70 mmol, 1 molar equivalent) and then butylamine (351 pL, 5 molar equivalents) was added dropwise. The reaction was stirred in the dark at room temperature for 6 days, and then worked up by dilution with 2N H2SO4 and extraction with ethyl acetate. Removal of the solvent gave the crude aminoquinone, purified by filtration on silica gel to obtain a dark powder (126 mg). (XVIII)

[0174] ((TR,6'R)-3-butylamino-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)-[l,T bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione)

[0175] A stirred solution of CBDV (200 mg, 0.70 mmol) in di chloromethane (5 mL) was treated with manganese (Ill)-acetate (162 mg, 0.69 mmol, 1 molar equivalent) and then n-pentyl (404 pL, 5 molar equivalents) was added dropwise. The reaction was stirred in the dark at room temperature for 6 days, and then worked up by dilution with 2N H2SO4 and extraction with ethyl acetate. Removal of the solvent gave the crude aminoquinone, purified by filtration on silica gel to obtain a dark powder (151 mg).

[0176] ((TR,6'R)-3-pentylamino-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)-[l,T bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione)

[0177] A stirred solution of CBDV (300 mg, 1.1 mmol) in di chloromethane (5 mL) was treated with manganese (Ill)-acetate (232 mg, 1.1 mmol, 1 molar equivalent), and benzylamine (610 pL, 5 molar equivalents) was then added dropwise. The reaction was stirred in the dark at room temperature for 6 days, and then was worked up by dilution with 2N H2SO4 and extraction with ethyl acetate. Removal of the solvent gave the crude aminoquinone, purified by filtration on silica gel to obtain a dark powder (290 mg).

[0178] ((rR,6'R)-3-benzyl-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)-[l,r bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione)

[0179] A stirred solution of CBDV (200 mg, 0.70 mmol) in di chloromethane (5 mb) was treated with manganese (Ill)-acetate (162 mg, 0.70 mmol, 1 molar equivalent), and isopentylamine (406 pL, 5 molar equivalents) was then added dropwise. The reaction was stirred in the dark at room temperature for 6 days, and then was worked up by dilution with 2N H2SO4 and extraction with ethyl acetate. Removal of the solvent gave the crude aminoquinone, purified by filtration on silica gel to obtain a dark powder (152 mg).

[0180] ((rR,6'R)-3-(3-methylbutyl)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)-[l,r bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione)

[0181] A stirred solution of CBDV (200 mg, 0.70 mmol) in di chloromethane (5 mb) was treated with manganese (Ill)-acetate (162 mg, 0.70 mmol, 1 molar equivalent), and neopentylamine (411 pL, 5 molar equivalents) was then added dropwise. The reaction was stirred in the dark at room temperature for 6 days, and then was worked up by dilution with 2N H2SO4 and extraction with ethyl acetate. Removal of the solvent gave the crude aminoquinone, purified by filtration on silica gel to obtain a dark powder (120 mg).

[0182] ((rR,6'R)-3-(2,2-dimethylpropyl)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-l-en-2-yl)- [1,1' bi(cyclohexane)]-2', 3, 6-triene-2, 5-dione)

[0183] Example 3. Activation of AMPK by compounds VII and XIII

[0184] The effect of compounds VII and XIII on the AMPK pathway was studied by pretreating the cells with the AMPK inhibitor Dorsomorphin (DS) (#S7306, Selleckchem). After treatment the cells were washed with PBS and proteins extracted in 50 pL of lysis buffer (50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 10 % glycerol, and 1 % NP-40) supplemented with 10 mM NaF, 1 mM Na3VO4, 10 pg / mL leupeptin, 1 pg / mL pepstatin and aprotinin, and 1 pL / mL saturated phenylmethyl sulfonyl fluoride (PMSF). Thirty to fifty micrograms of proteins were boiled at 95 °C in Laemmli buffer and electrophoresed in 10 % SDS / PAGE gels. Separated proteins were transferred to polyvinylidene difluoride (PVDF) membranes (24 V for 30 minutes) which were blocked using tris-buffered saline (TBS) solution containing 0.1 % Tween 20 and 5 % non-fat dry milk for 1 hour at room temperature. Immunodetection of specific proteins was carried out by incubation with primary antibody against phospho-AMPK (1 : 1000, #2535S, Cell Signalling Technology), total-AMPK (1 :1000, #ab80039, Abeam) and P-actin (1 : 10.000, #ab49900, Abeam), overnight at 4 °C. After washing the membranes, horseradish peroxi dase-conjugated secondary antibody was added and detected by chemiluminescence system (GE Healthcare Europe GmbH). Compounds VII and XIII induced the phosphorylation and activation of AMPK, which was prevented by DS (Figures 1A and IB).

[0185] Example 4. Effect of compounds VII and XIII in Sirtuin (Sirtl) expression and activation

[0186] To explore the modulation of Sirtl expression and activity by compounds VII and XIII (Fig 2A and 3A) cells were seeded and stimulated with compounds VII and XIII for 60 min and western blots performed as described in Example 3. Immunodetection of specific proteins was carried out by incubation with primary antibody against specific proteins was carried out by incubation with primary antibody against Sirtuin 1 (1 :1000, #8469, Cell Signalling Technology), Visfatin (1 : 1000, #ab236874, Abeam) and P-actin (1 : 10.000, #ab49900, Abeam) overnight at 4 °C. Compound VII induced the expression of the nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase Sirtl and the expression of the nicotinamide phosphoribosyl transferase (NAMPT) (Figure 2A). Sirtl activity was determined with the Sirtl Activity Assay Kit (Fluorometric) (#ab 156065, Abeam) that allows the rapid and sensitive evaluation of Sirtl inhibitors or activators using purified Sirtl, according to the manufacturer’s instructions. For NAD / NADH Assay EA.hy926 (2 x 106 / well) were seeded and 24 hours later, the compounds VII and XIII (were added at different concentrations. After 4 hours, NAD+and NADH were measured with a commercially available NAD+ / NADH assay kit (#ab65348, Abeam) according to the manufacturer’s protocol. Compounds VII and XIII increased the Sirtl activity and the generation of NAD+(Figure 2B-2C and 3B-3C). The effect of compound VII on glucose-induced repression of Sirt 1 was detected in EA.hy926 cells incubated with high concentration of glucose (80 mM). Western blots were performed as in Example 3. Compound VII restored the expression of Sirtl in endothelial vascular cells (Figure 2D).

[0187] Example 5. Compounds VII and XIII induce HRE-Luc activation in an AMPK- and Sirtl-dependent manner.

[0188] Transactivation luciferase assays were used to explore the influence of Compounds VII (Fig. 4A) and XIII (Fig. 4B) on AMPK, and Sirtl pathways. NIH-3T3-HRE-luc cells were seeded in 96-well plates and after 24 hours were pre-treated with the different inhibitors (DS or EX527) for 30 minutes and then with the compounds for 6 hours. After stimulation, the luciferase activities were quantified using a Luciferase Assay kit (#E1483, Promega, Madison, WI, USA). The use of the AMPK inhibitor DS, the Sirtl inhibitor EX527 and the combination of these last two inhibitors significantly harmed the ability of Compounds VII and XIII to activate the EPO gene promoter, showing a connection between these pathways in its mechanism of action (Fig 4A and 4B). Example 6. Compounds VII and XIII prevent endothelial cells senescence and restores Sirtl expression impaired by prooxidative stress.

[0189] HMEC-1 cells were treated with either Compound VII (Fig. 5) or XIII (Fig 6) at different concentrations for 1 h, H2O2 was added for 4 hours on days 2 and 5 and then culture up to 7 days. SA-b-gal staining was performed according to manufacturer instructions (#9860, Cell Signalling). The pre-treatment with Compound VII for 1 h was able to reduce the SA-P-gal-stained cells (Fig. 5A) and the expression of PAI-1 protein, a senescence marker, increased after H2O2 treatment at day 7 as compared with the control group (Figure 5D). In addition, Sirtl protein expression was reduced in senescent cells but was recovered with the treatment with Compound VII (Figure 5B). The pre-treatment with Compound XIII for 1 h was able to reduce the SA-P-gal-stained cells (Fig. 6A) and the expression of p21 protein, a senescence marker, increased after H2O2 treatment at day 7 as compared with the control group (Figure 6B). In addition, Sirtl protein expression was reduced in senescent cells but was recovered with the treatment with both compounds (Fig. 5B and 6B.). Western blot were performed as described in Example 3 and immunodetection of specific proteins was carried out by incubation with primary antibody Sirtuin 1 (1 :1000, #8469, Cell Signalling Technology), PAI-1 (1:1000, #ab222754, Abeam), p21, and a-tubulin (1 :5000, #T9026, Sigma).

[0190] Example 7. Compound VII protects vascular endothelial cells from cytotoxicity induced by H2O2, Oxo-LDL and Glucose

[0191] Cell viability was determined using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. In brief, EA.hy926 cells were seeded in 96-well plates and 24 hours later treated with the inhibitors, next, the cells were exposed to H2O2, glucose or oxo-LDL in the absence or the presence of Compound VII. Finally, MTT at 5 mg / mL was added for 4 h. After MTT incubation, the culture medium was removed, DMSO was added to the plate, and absorbance was measured at 560 nm using a Microplate Reader (Tecan). Cell viability was expressed as a percentage relative to control. Compound VII shows cytoprotection in endothelial vascular cells after treatment with H2O2, Oxo-LDL and Glucose (Fig 7A-C). Example 8. Antiinflammatory activity of compound VII in vascular endothelial cells

[0192] EA.hy926 (2.5 x 103 / well) were seeded onto glass coverslips in 24-well plates. Cells were pre-stimulated with Compound VII at several concentrations for 1 hour and incubated for 24 hours with interleukin 1 beta (IL 1 P) (R&D Systems) plus tumor necrosis factor alpha (TNFa) (R&D Systems) (for VCAM study) or interleukin 6 (IL-6) (R&D Systems) plus TNFa (for tight junction proteins study). Cells were then washed with PBS and fixed with 4 % formaldehyde for 10 minutes at room temperature (RT). After fixation, cells were washed twice with PBS, permeabilized with 0.5 % Triton X-100 in PBS at RT for 5 minutes and blocked in PBS with 3 % BSA for 1 hour. Cells were incubated overnight at 4 °C with the following primary antibodies diluted in PBS with 3 % BSA: rabbit monoclonal anti-VCAMl (1 : 100, #abl34047, Abeam), rabbit polyclonal anti-ZO-1 (1: 100, #10222233, Invitrogen; Carlsbad, CA, USA) or CLD1 (1 :100, #abl5098, Abeam) Next, cells were washed three times with PBS and incubated with the secondary antibody anti-rabbit Texas Red (1:100, #A-6399, Thermo Fischer Scientific) or antimouse Alexa 488 for 1 hour at RT. Finally, coverslips were mounted with Vectashield Mounting Medium with 4',6-diamidino-2-phenylindole (DAPI) (Vector Laboratories, Burlingame, CA, USA) for nuclear staining. Images were acquired using a spectral confocal laser-scanning microscope LSM710 (Zeiss) with 25x / 0.8 Plan-Apochromat oil immersion lens.

[0193] Compound VII strongly inhibited the expression of VCAM-1 in EA.hy926 vascular endothelial cells stimulated with TNFa plus IL-ip. Several cytoplasmic proteins have been described to associate with TJ transmembrane proteins and to contribute somehow to TJ integrity in epithelial and vascular endothelial cells. Among them, zonula occludens-1 (ZO-1) expression and distribution in endothelial cells is decisive in the process of formation of tight junctions between endothelial cells. ZO-1 forms heterodimers with ZO-2 and ZO-3 and interacts with claudins at TJs, then anchoring this multimolecular complex to the actin cytoskeleton. Compound VII clearly restored the reduced expression of ZO-1 and CLD1 in EA.hy926 vascular endothelial cells treated with the proinflammatory cytokines (TNFa + IL-6) (Fig. 8). Example 9. Compounds VII and XIII induce arteriogenesis in vivo.

[0194] Sirtl expression is clearly in the vascular endothelium of human samples obtained from patients suffering from critical limb ischemia that were subjected to vascular surgery (Fig 16). Since compounds VII and XIII are inducers and activators of AMPK / Sirtl the in vivo effects of compounds VII and XIII is studied in a model of critical limb ischemia (CLI) that also courses with accelerated vascular senescence was assessed in male C57-BL / 6 mice aged 10-12 weeks. The mice were randomly divided into 2 groups (CLI group and sham group). In CLI group involved exposure of the left femoral artery through a vertical 0.5-1 cm skin incision under a stereotactic microscope (Leica). The femoral artery and its side branches were double ligated with 6-0 silk sutures (Ethicon) immediately distal to the inguinal ligament and proximal to the popliteal bifurcation. Femoral nerves were carefully preserved. A similar surgery without ligation of the femoral artery was performed on the sham controls. The CLI group was treated with compound VII (20mg / kg) by oral gavage every day until the end of the study and the sham control group was treated with vehicle. After 10 and 28 days, tissues were collected for vascular casting, histological and gene expression analysis.

[0195] For vascular casting (Microfil perfusion) mice were anesthetized and injected 1000 UI of heparin (i.p.). After 10 minutes, the mice were euthanized, the thorax was opened, and the aorta was exposed. A catheter was carefully inserted into the descending aorta and manually fixed with sutures. Then mice were perfused with PBS (37 °C, 80 ml) containing heparin and nitroglycerin to remove the blood and enhance the vasodilatation of the arteries.15 ml of Microfil (#MV-112 [white]; Flow Tech Inc.) was prepared and then injected. The Microfil polymerized overnight at 4 °C, and the collagen gels and underlying abdominal musculature were harvested and clarified in graded glycerol solutions (40 %-100 % glycerol in water; glycerol increased by 20 % at 24-hour intervals). The clarified specimens were viewed on a dissecting microscope. After Microfilm polymerization, the animals were mounted in a standard sample holder inside a Bruker SkyScan 1172 high-resolution microtomography machine (Bruker microCT, Kontich, Belgium). The X-ray source was set to a voltage of 50 kV and a current of 498 pA with a 0.5-mm Al filter in the beam path with an angular increment of 0.3 °. Data were transferred to a computer with NRecon, CTAn, CT Vol software, (Bruker), Imaged (http: / / rsb.info.nih.gov / ij / ) and 3DSlicer v.3.4.0 open-source software (https: / / pubmed.ncbi.nlm.nih.gov / 22770690 / ) was using to analyze vessel numbers, diameter, area, and volume, as well as arterial density.

[0196] Compound VII treatment clearly increased arteriogenesis in the ligated limb compared to the ligated limb without treatment. However, in the case of not ligated limb treated with Compound VII much less collateral formation was observed, in comparison with control limb (Figure 9A). Similar results were obtained in mice 28 days after ischemia (Figure 9B). Compound VII did not induce arteriogenesis in the nonischemic limbs, indicating that the effects of Compound VII is specific for hypoxic tissues where endothelial vascular senescence assessed by the lack of Sirtl expression is observed (Figure 13). Similarly, Compound XIII also increased arteriogenesis in the ligated limb compared to the ligated limb without treatment (Fig. 15),

[0197] High-resolution microcomputer tomography (mCT) images performed 28 days after femoral occlusion showed that the distribution of vessels in the mouse limbs was similar between the untreated (Control) and treated groups (C + Compound VII). In contrast, the number of vessels were significantly reduced in the ligated limb (CLI) and fully restored after treatment with Compound VII (CLI+ Compound VII) (Figure 10A-B).

[0198] Example 10. Effects of compound VII in endothelial cell proliferation during Hind Limb Ischemia

[0199] One of the most essential events for augmenting arteriogenesis is vascular endothelial cell proliferation. To identify proliferation. The limb muscles containing the Gastrocnemius muscles (GM) from CLI and Control mice were collected and progressively frozen in isopentane (2-methylbutane) (Sigma) suspended liquid nitrogen to preserve optimal skeletal muscle morphology. Muscle samples were mounted in OCT compound (ProSciTech) and cut at -21 °C into 5 pm -thick sections of muscle fibers oriented in a transverse direction. The slides were fixed at -20 °C in methanol-acetone for 8 minutes. The slides were boiled for 10 minutes in sodium citrate buffer (10 mM, pH 6.0) for antigen retrieval. The sections were washed three times in PBS containing 0.1 % Triton X-100 (Sigma). Nonspecific antibody -binding sites were blocked for 1 hour at room temperature with 3 % BSA in PBS (Sigma). Next, the sections were incubated overnight at 4 °C with the following primary antibodies diluted in PBS with 3 % BSA: anti-cluster of differentiation 31 (CD31) (1 : 100, #ab28364, Abeam) and anti-Ki67 (1:100, #ab 15580, Abeam). The next day sections were washed three times for 10 minutes with a wash buffer and incubated in darkness at room temperature for 1 hour using anti-rabbit Texas Red (1: 100; &A-6399, Thermo Fischer Scientific) or anti-mouse Alexa 488 1 : 100; #A-11029; Invitrogen). The slides were then mounted using Vectashield Antifade Mounting Medium with DAPI (Vector Laboratories). All images were acquired using a spectral confocal laser-scanning microscope LSM710, (Zeiss, Jena, Germany) with a 20 x / 0.8, 25, 40, or 63 x / 0.8 Plan-Apochromat oil immersion lens and quantified in randomly chosen fields using ImageJ software (http : / / rsb web . ni h . gov / ij / ) . Endothelial cells proliferation index was calculated by CD31 / Ki67 positive cells (Wessel area).

[0200] Compound VII therapy enhanced cell proliferation in the gastrocnemius muscle. In Figure 11, representative immunofluorescent staining for the cell proliferation marker Ki67 and CD31 in either control or compound VII -treated tissues is observed. Oral compound VII increased double colocalization of CD31+ / Ki67+staining during ischemia compared with control tissue with or without treatment, indicating that most proliferating cells were in vascular endothelium. The proliferation index was significantly augmented in ligated limb compound VII -treated as in comparison with no treated ligated limb or control- treated limb.

[0201] Example 11. Effects of compound VII on tissular fibrosis during CLI

[0202] Several studies supported the involvement of fibrosis in the pathophysiology of PAD after femoral occlusion and the antifibrotic effect of compound VII in ischemic tissue (28 days after femoral ligation) was evaluated by Tenascin-C (TNC) immunofluorescent staining, a tissue biomarker marker for fibrosis. IHC studies were performed as described in Example 10 using anti-rat Tenascin (TNC) (1: 100, dilution, &MAB2138, R&D Systems). All images were acquired using a spectral confocal laser-scanning microscope LSM710, (Zeiss, Jena, Germany) with a 20z / 0.8 Plan-Apochromat lens and quantified in randomly chosen fields using ImageJ software (http : / / rsbweb . nih, gov / ij ) .

[0203] The treatment with oral formulation of compound VII alleviated the deposition of TNC in ischemic muscles relative to non-treated ischemic muscle. No expression of TNC was found in the control mattes, with or without treatment (Figure 12). Example 12. Effects of compound VII on Sirtl expression, as a marker of senescence, in CLI mice

[0204] IHC studies were performed as described in examples 10 and 11 by incubation with a primary antibody against Sirtuin 1 (1:1000, #8469, Cell Signalling Technology). Senescence was induced in the ischemic limb (Sirtl reduced expression) and it was completely restored by the treatment with compound VII (Figure 13).

[0205] Example 13. Sprouting effect of compounds XIII, XVI and in the aortic ring model.

[0206] The effect of representative aminoquinone cannabinoids disclosed in the present invention on arteriogenesis was assessed in the aorta ring assay. This assay is a physiologically important assay with strong advantages over other in vitro procedures supporting cells because in this assay are included in the formation of micro vessels. The strength of the assay is the adjustment to diverse applications, such as testing of several molecules, including small drugs. The thoracic aorta was sectioned into 1-mm long aortic rings and cultured in Opti-MEM (Thermo Scientific) with 100 U / mL penicillin and 100 pg / mL streptomycin overnight. Aortic rings were encapsulated in growth factor reduced Matrigel (Coming, United States) in 24-well plates. The aortic ring was then cultured in Opti-MEM supplemented with 2.5% FBS, 30 ng / mL VEGF, as positive control or with representative aminoquinone cannabinoids (5 pM) in a humidified 37°C, 5% CO2 incubator for 10 days. The rings were fed with growth medium every 2 days. Images were acquired by using a microscope and analyzed with NIH Imagel software (http: / / rsbweb.nih.gov / ij / ). Sprouts were counted during the exponential growth phase to obtain angiogenic response data. Figure 14 indicates that representative aminoquinone cannabinoids significantly induced arteriogenesis, indicated by the formation of new sprouts as well as sprout area. In addition, similar results shown the mouse aorta ring incubated with positive control (VEGF).

[0207] Example 14. Solubility of cannabinoid aminoquinones

[0208] Kinetic solubility study of the compounds in a medium of PBS pH 7.4 using UPLC-PDA for quantification. Stock Solutions of the test compounds were prepared at a concentration of 100 mM in DMSO or DMF. Preparation of each sample (two replicates per compound): a volume of 15 pL of sample stock solution 100 mM (Table II) was transferred to a 5 mb vial containing 2985 pL of PBS pH 7.4. Co-solvent content in final dilution is 0.5%. The sample was stirred at 800 r.p.m. for 2 hours on a thermomixer at room temperature. The concentration of the test compound in the final incubation volume was 0.5 mM. At the end of the incubation period, each sample was filtered through a 0.2 pm hydrophilic PTFE syringe filter and analysed by UPLC-PDA against the corresponding calibration curve. Solubility criteria: Low Solubility: <10 pg / mL; Moderate Solubility: 10 to 60 pg / mL; High Solubility: >60 pg / mL; <LLOQ (lower limit of quantitation). Table II shows that compounds XI, XIII and XVI have improved solubility compared to compounds IV, V, VII and IX.

[0209] Table II. Solubility

[0210] In view of the above, it will be seen that several objectives of the disclosure are achieved, and other advantages attained. As various changes could be made in the above methods and compositions without departing from the scope of the disclosure, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

[0211] As used herein, in particular embodiments, the terms “about” or “approximately” when preceding a numerical value indicates the value plus or minus a range of 10%. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. That the upper and lower limits of these smaller ranges can independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0212] The indefinite articles “a” and “an,” as used herein in the specification and in the embodiments, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0213] The phrase “and / or,” as used herein in the specification and in the embodiments, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements can optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0214] As used herein in the specification and in the embodiments, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the embodiments, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the embodiments, shall have its ordinary meaning as used in the field of patent law.

[0215] As used herein in the specification and in the embodiments, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements can optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

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Claims

CLAIMS1. A compound of formula (I) or a derivative thereofwherein,R1is a Ci-C6unbranched or branched alkyl that is optionally substituted at its terminus with a group selected from a 5- or 6-membered heterocycloalkyl, a phenyl, an amino group, NH(C0)CH3, OH, or C1-C3 alkoxy, wherein the 5- or 6- membered heterocycloalkyl can be optionally substituted with C1-C4 alkyl; andR2is CH3or CH2CH2CH3; for use in the treatment or prevention of chronic venous insufficiency, Raynaud’s syndrome, peripheral microangiopathies, non-cancerous vascular malformations, acute peripheral arterial occlusion, metabolic bone disorders, sarcopenia, fracture healing, osteoarthritis, vitiligo, rosacea, atopic dermatitis, melasma, skin aging, non- fibrotic chronic kidney disease, glomerular disorders, renal tubular acidosis, mitochondrial myopathies, age-related macular degeneration, rare vascular disorders, frailty syndrome, inherited metabolic and vascular disorders.

2. The compound of formula (I) for use according to claim 1, wherein the treatment or prevention includes the activation of the AMP-activated protein kinase / Sirtuin 1 pathways.

3. The compound of formula (I) for use according to claim 2 or 3, wherein the disease is associated with cellular senescence.

4. The compound of formula (I) for use according to any of the claims 1-3, wherein the heterocycloalkyl is a five- or six-membered ring containing one or more heteroatoms selected from N, O, and S.

5. The compound of formula (I) for use according to any of the claims 1 to 4, wherein the heterocycloalkyl is selected from the group consisting of: tetrahydrofuran, pyrrolidine, or thiophene, piperidine, pyridine, or tetrahydrothiopyran, 1,4 dioxane, imidazole, pyrazole, pyrimidine, pyridazine, pyrazine, oxazole, thiazole, or morpholine.

6. The compound of formula (I) for use according to any of the claims 1 to 5, wherein the heterocycloalkyl is substituted.

7. The compound of formula (I) for use according to any of the claims 1 to 6, wherein the compound is selected from the group consisting of:V VIXXI XXII8. A compound of formula (I) or any pharmaceutical acceptable salt, ester or solvate thereof:selected from the group consisting of:10 XVII XVIIIXXI XXII.

9. A pharmaceutical composition comprising at least one compound according to claim 8.

10. The compound of formula (I) according to claim 8 or a pharmaceutical composition according to claim 9 for use as a medicament.

11. The pharmaceutical composition according to claim 9 or 10 comprising at least one inactive ingredient or excipient.

12. The pharmaceutical composition according to claim 9, 10 or 11 comprising at least one compound selected from the group consisting of: carriers, cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers and antioxidants.

13. The compound of formula (I) of claim 8 or the pharmaceutical composition of any one of claims 9-12 for use in the treatment or prevention of diseases.

14. The compound of formula (I) of claim 8 or the pharmaceutical composition of any one of claims 9-12 for use of claim 13, wherein the treatment or prevention includes the activation of the AMP-activated protein kinase / Sirtuin 1 pathways.

15. The compound of formula (I) of claim 8 or the pharmaceutical composition of any one of claims 9-12 for use according to claim 13 or 14, wherein the disease is associated with cellular senescence.

16. The compound of formula (I) of claim 8 or the pharmaceutical composition of any one of claims 9-12 for use in the treatment or prevention of chronic venous insufficiency, Raynaud’s syndrome, peripheral microangiopathies, non-cancerous vascular malformations, acute peripheral arterial occlusion, metabolic bone disorders, sarcopenia, fracture healing, osteoarthritis, vitiligo, rosacea, atopic dermatitis, melasma, skin aging, non-fibrotic and fibrotic chronic kidney disease, glomerular disorders, renal tubular acidosis, mitochondrial myopathies, age-related macular degeneration, rare vascular disorders, frailty syndrome, inherited metabolic and vascular disorders, , acute kidney disease, vascular dementia, type 2 diabetes, obesity, and / or traumatic brain injury.

17. The compound of formula (I) for use according to claim 13, wherein the treatment or prevention includes the activation of the AMP-activated protein kinase / Sirtuin 1 pathways.

18. The compound of formula (I) for use according to claim 13 or 14, wherein the disease is associated with cellular senescence.

19. A unit dosage form comprising the compound of formula (I) of claim 8 or the pharmaceutical composition of any one of claims 9-12.

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