AU2015101671A4 - Combination therapy comprising a PI3, AKT kinase or mTOR inhibitors - Google Patents

Abstract

The present invention provides compounds, and pharmaceutically acceptable salts. Also provided are methods of using the compounds of this invention as a combination therapy comprising a P13, AKT kinase or mTOR inhibitors for the prevention and treatment of hyperproliferative diseases such as cancer, insulin resistance, diabetes, arthritis, obesity, and neurological conditions and diseases.

Description

Complete Specification Innovation Patent APPLICANT: Julie Anne-Marie van Eps Invention Title: Combination therapy comprising a P13, AKT kinase or mTOR inhibitors The following is a full description of the invention, including the best method of performing it known to me. 1 Combination therapy comprising a P13, AKT kinase or mTOR inhibitors The Invention is a IRS-1, P13, AKT kinase or mTOR inhibitors. This is an Australian Patent with a priority date as of the date of filing, the entire disclosure of which is included herein by way of reference. Field of the Invention [0001] The invention relates to novel inhibitors of serine/threonine protein kinases (e.g. AKT and related kinases), pharmaceutical compositions containing the inhibitors and methods for preparing these inhibitors that are useful for the treatment of hyper-proliferative diseases such as cancer and inflammation, insulin resistance, diabetes, neurological conditions and diseases. [0002] The insulin receptor substrate (IRS)-1/phosphatidylinositol (P13) kinase pathway also results in diminished glucose uptake and utilization in insulin target tissues. The regulation and inhibition of IRS-1/P13K/AKT/mTOR pathway constitutes in particular a novel and powerful mechanism of action by the use of a powerful combined therapy that provides a synergistic effect (the invention) for the treatment of cancer, inflammation, insulin resistance, diabetes, obesity, arthritis, neurological conditions and diseases. BACKGROUND OF THE STATE OF THE ART OF THE INVENTION [0003] Serine/threonine kinase Akt, also known as protein kinase B (PKB), has emerged as one of the most frequently activated protein kinases in human cancer. The phosphatidylinositol 3-kinase (P13K) pathway creates a shift form oxidative to glycolytic metabolism, one of the most common changes found in cancer, regardless of the type of cancer[1]. [0004] Serine phosphorylation of IRS proteins can reduce their ability to attract P13-kinase, thereby minimizing its activation. A number of serine kinases phosphorylate serine residues of IRS-1 and weaken insulin signal transduction. Mitochondrial dysfunction has been found to trigger activation of several serine kinases, leading to a serine phosphorylation of IRS-1[2]. 2 [0005] Metabolic and anti-apoptotic effects of insulin are mediated by the signaing pathway involving IRS proteins, phosphorylation, and activation of phosphatidylinositol (PI) 3-kinase, Akt and mTOR. TNFa, an agent responsible for cachexia, has been shown to be increased in adipose tissue of obese and insulin resistant humans and animals [2]. TNFa has also been shown to block insulin signalling by promoting serine phosphorylation of IRS-1 with a resultant decline in IRS-1 -associated P13-kinase activity. [0006] Activators of P13K-Akt signalling play a central role in glucose metabolism and homeostasis, and P13K and c-Myc facilitate increased glucose uptake through glycolysis. Lactate dehydrogenase maintains glycolytic flux by converting excess pyruvate to lactate, regenerating NAD. Coupling between Akt-mediated cellular energy metabolism, cell survival and proliferation. The tumor microenvironment promotes cancer cell growth and metastasis through metabolic changes that result in cytokine secretion and extracellular remodelling[3], [4]. [0007 Cancer cells shunt pyruvate metabolism away from mitochondrial oxidative phosphorylation toward the conversion of pyruvate to lactic acid[5]. Fermentation is a metabolic process that converts glucose to acids, gases or alcohols [5]. [0008] An increase in lactate production is also seen in oxygen starved muscles cells as well as adequately oxygenated cells when respiration is inhibited either by respiratory poisons or mutations in key respiratory enzymes. Whether oxygen is withdrawn from the cell or oxygen is prevented from reacting by a poison, the outcome is the same [6]. Normal tissues convert glucose they consume, which is reduced to pyruvate during the process of glycolysis. [0009] Lactate is also produced in normal tissues under low oxygen conditions, and tumor cells also produce lactate in hypoxic conditions through anaerobic glycolysis[7]. In the absence of oxygen, glucose undergoes fermentation to lactic acid, which lowers the cell pH to 7 and further, down to 6.5. In the acid media a number of significant changes take effect, the DNA loses its positive and negative radical sequence, the amino acids entering the cell are altered, and the RNA is also changed whereby the cell completely loses its control mechanism, and as a result chromosomal aberrations are 3 likely to occur[8]. [0010] The phosphatidylinositol (PI) 3-kinase (P13K) pathway is one of the signaling pathways that exerts its effect on numerous cellular functions including cell cycle progression, proliferation, motility, metabolism and survival. Survival factors, such as platelet derived growth factor (PDGF), nerve growth factor (NGF), and insulin-like growth factor-1 (IGF-1), promote cell survival under various conditions by inducing the activity of P13K. [0011] Activated P13K leads to the production of phosphatidylinositol, which in turn binds to, and promotes the activation of, the serine/ threonine kinase Akt, which displays a great importance of protein kinases in the processes of signal transduction and regulation of cellular functions. Apoptosis (programmed cell death) plays essential roles in the pathogenesis of many diseases, such as neurological conditions and diseases, cardiovascular diseases and cancer. Technical problems [0012] According to WHO, cancer is a leading cause of death worldwide, accounting for 7.6 million deaths in 2008. Despite various, often conflicting public information, WHO reports that by 2030, the number of people being diagnosed with cancer is expected to increase to 21 million, and deaths from cancer worldwide are projected to continue to rise, with an estimated 13.1 million deaths in 2030 globally. Despite recent advances in the understanding of the genesis, progression and treatment of cancer, much still needs to be done to improve the overall prognosis of cancer patients. [0013 The discovery of the many thousands of genes and mutations occurring in many different cancers has led to the perception that cancer is not one single disease, but a collection of many different diseases. There are many theories as to the cause of cancer, such as aberrant metabolism, respiratory insufficiency due to mitochondria dysfunction[4]; a genetic disease[9]; and over production of ROS due to oxidative stress[10]. Regardless of the cause, and what is not in dispute is that the majority of neoplastic cells feature aberrant glucose metabolism, when respiration is shunted away from oxidative phosphorylation towards towards glycolysis, first discovered by Otto Warburg (1924)[11]. 4 [0014] In normal cells, glycolysis is suppressed in the presence of oxygen[1]. In human tumors as compared to normal tissue, the microcirculation is compromised and tissue oxygenation is not regulated according to demand, resulting in a hypoxia. Study results have shown PO2 of the tissue is low, which is linked to size (a tumor with a volume of 2 ml is extremely hypoxic), often close to 0 mm Hg, and heterogeneous[12]. As evidenced by a CT-PET positive scan, most, if not all cancer cells are glycolytic, have a higher requirement for glucose as an energy source, producing increased lactate, resulting in hypoxia and a reduction in cellular pH. Long term evidence has demonstrated that abnormal pH values trigger inappropriate cell function, growth and division and are associated with common diseases such as cancer[1 3]. [0015] Glycolysis is a metabolic process by which one molecule of glucose is catabolised by two molecules of pyruvate producing a net gain of two ATP. Altered glucose metabolism is the basis of positron emission tomography (PET) which uses the glucose analogue tracer fluorodeoxyglucose, a widely used clinical application for tumor diagnosis and monitoring[1 4]. The increased glucose uptake imaged with PET occurs as a result of the upregulation of glucose transporters GLUT 1 and GLUT3, and hexokinases I and II [15]. [0016] Tissue hypoxia can occur during diseases such as chronic inflammation, vascular disease, and cancer[16]. Hypoxia is a major feature of solid tumors and is shared by all cancer types including haematological cancers[7]. Hypoxic and acidic conditions provide cancer cells with a growth advantage, and are associated with a decreased overall survival[1 7]. [0017] Hypoxia induces erythropoietin (EPO) in renal cells, which increases the production of haemoglobin and tyrosine hyroxlyase synthesis in neural cells, which are involved in the production of catecholamines initiated by a stress response [7]. As a consequence, intracellular pH displays a significant impact on human physiology, by affecting critical roles in enzyme and tissue activities including proliferation and apoptosis, ion transport, endocytosis and multi-drug resistance[13]. [0018] The glycolytic phenotype initially arises as an adaptation to local hypoxia. One of the identified mechanisms for the high rate of glycolysis is 5 over activation of hypoxia Inducible Factor-1 (HIF-1) which is activated in prolonged hypoxic and responsible inflammatory conditions[18], [17], [19],[18] [20],[21]. The transcriptional up-regulation of genes facilitated by HIF-1 and HIF-2, enhances tissue perfusion and anaerobic ATP generation through glycolysis [16]. [0019] Lactate production engaged through glycolysis has been shown to trigger HIF-1. HIF-1 is a heterodimer that consists of the HIF-1, and the aryl hydrocarbon receptor nuclear translocator (ARNT), which is also known as HIF-2[17]. Whilst low oxygen levels can be fatal for normal cells, the activation of HIF-1 up-regulates the expression of over 80 genes that are involved in glucose metabolism, cell survival, angiogenesis, cancer progression and invasion [22]. [0020] Hypoxia has a profound impact on transcription, and the consequences of hypoxia-induced or hypoxia-repressed gene expression have significant implications in disease processes such as chronic inflammation and cancer development [16]. Genes under the control of HIF-1 include those involved in vasodilatation, (nitric oxide synthase), glycolysis (glucose transporters GLUT 1 and GLUT 3), angiogenesis (VEGF) and enhanced blood oxygenation (EPO). [0021] The expression of such genes is crucial for tissue survival and adaptation in ischaemic disease, and are essential for tissue oxygen delivery [16], [23]. Further, metabolic regulation triggered by HIF-1 also activates tumor suppressors and oncogenes such as p53, c-Myc, Ras and Akt [7]. Hypoxia precipitates in the invasive potential of tumor cells. [0022] HIF-1 production is associated with the loss of E-cadherin, which would normally provide inhibitory and suppressive capabilities of cells to metastasize[7]. HIF-1 promotes angiogenesis by up-regulating VEGF expression to stimulate endothelial cell proliferation to form new blood vessels [22]. Tumor cells secrete lactic acid, which impairs immunity by inhibiting leukocytes, and increased lactate production produces a low pH and acidotic environment that inhibits cytokines such as tumor necrosis factor from monocytes[22]. [0023] Oxidative stress damages endothelial cells directly, causing the loss of peritubular capillaries, resulting in hypoxia, which is precipitated by 6 inefficient cellular respiration. Thus, angiotensin II induces renal hypoxia via both haemodynamic and non-haemodynamic mechanisms[24]. Ions and minerals need to be stored and reabsorbed into the peritubular capillaries. The ions that are eventually excreted as waste; are secreted from the capillaries into the nephron to the bladder; and passed through urine. [0024] The majority of exchange through the peritubular capillaries occurs because of chemical gradients, osmosis and Na+ pumps. Mineral and water balance is crucial for the regulation of pH[24]. The renin-angiotensin aldosterone (RAAS) system is activated in hypoxia[17]. To highlight the importance of the secretion of the angiogenic enzymes, activation of the renin angiotensin system (RAS), or the RAAS are hormone systems that regulate water and mineral balance, as well as blood pressure. Whilst RAS has been traditionally associated with kidney function, RAS has been identified in most organs. In addition, complement 3 activates the renal RAS by induction of epithelial-to-mesenchymal transition (EMT)[25],[26]. [0025] Further, aldosterone induces EMT and is triggered by mitochondrial derived oxidative stress[27]. Non-hypoxic stimuli, including hormones and growth factors, are also important HIF-1 activators in the vasculature. Angiotensin II is the main effecter hormone in RAAS, also a potent HIF-1 activator in vascular smooth muscle cells [28]. [0026] Further, the generation of mitochondrial ROS is also implicated in HIF-1 activation in non-hypoxic conditions[28]. Therefore, kidney function through sufficient water and mineral balance is critical for the regulation of the angiotensin system, pH and hypoxic modulators such as HIF-1. [0027] The upregulation of glycolysis even in the presence of oxygen, can occur through mutations or epigenetic changes such as alteration in the methylation patterns[15]. Epigenetic mechanisms include DNA methylation, histone modifications and noncoding RNAs, all of which are crucial for the stable propagation of gene activity [29]. [0028] Epigenetic mechanisms, and specifically DNA methylation plays an important role in cellular processes, including cell differentiation, DNA repair and cell replication[30]. DNA methylation forms the basis of chromatin structure which enables cells to form the many characteristics from a single immutable sequence of DNA [31], [32],[33]. Aberrant epigenetic events are a 7 hallmark of cancer[34], [35]. [0029] Histone acetylation plays a key role in modulating chromatin structure and function. Histone modifications, such as phosphorylation, acetylation, or methylation are histone codes for chromatin packing and transcription[36]. Histone acetyltransferases (HATs) and deacetylases (HDACs) are responsible for the addition and removal of acetyl groups, and function antagonistically to control histone acetylation. [0030] In cancer, the disruption of the balance between control histone acetylation. In cancer, the disruption of the balance between HATs and HDACs directly contributes to transcriptional inactivation of tumor suppressor genes. In addition, HATs and HDACs facilitate a direct function in the activation and deactivation of genes[36]. Epigenetics regulates gene expression, which can be influenced by environmental factors such as toxins, radiation, infectious agents and nutritional status, which may activate chemical switches that regulate gene expression[37],[38]. [0031] DNA methylation is a form of epigenetic modification that occurs within one-carbon metabolism that is divided into two main branches. One consists of reactions that involves purine and thymidine synthesis, and the second involves synthesis of methionine and S-adenosylmethionine (SAM) for protein and polyamine synthesis required for methylation reactions [39]. [0032] The enzyme that directs methyl groups from the first branch to the second is methylenetetrahydrofolate reductase (MTHFR). Within the cycle, methionine is converted to S-adenosylmethionine (SAM), the primary methyl donor. MTHFR is one of the most important enzymes for folate metabolism. [0033] MTHFR is required for the synthesis of 5-methyltetrahydrofolate (5 MTHF), which is the carbon donor in the remethylation of homocysteine to methionine [40]. In methylation, SAM donates its methyl group to the methyl acceptor, and converts to S-adenosylhomocysteine (SAH). It has long been recognised that altered methionine metabolism has been a characteristic trait of malignant cells, and that DNA methylation patterns are altered in cancer [41]. [0034] Hypomethylation has been found to be an early event in carcinogenesis, and may induce one of the first epigenetic alterations [42]. A deficiency in methyl group inhibits both histone methyltransferases and DNA 8 methyltransferases [43],[44]. [0035] Adequate levels of SAM and SAH are necessary to prevent inhibition of other critical DNA methyltransferase enzymes. The methylation of DNA is reliant upon a group of methyltransferases (DNMTs), DNMT1, 2 and 3. DNMT1 is referred to as the methylation maintenance enzyme, and completes the methylation pattern of each replicating DNA strand. As hypomethylation continues to occur, DNMT1 further down regulates and causes the protective coating on DNA, histones to unwind [45]. [0036] It has been demonstrated in both in vitro and in vivo studies that BRCA1 deficiency leads to global DNA hypomethylation and chromatin abnormalities. Studies have also shown that DNMT1 is a transcriptional target of BRCA1 [45]. [0037] During the one carbon metabolism cycle, several enzymes are catalysed in the presence of dietary micronutrients that act as cofactors, which include folate, vitamin B12, B2, B6, betaine and choline[46], [47]. Impaired one-carbon metabolism can arise from a folate deficiency, secondary B vitamin deficiencies, and or genetic variations that influence cellular folate accumulation [47]. [0038] Vitamin B12 deficiency diminishes methionine synthase, as well impairs nucleotide biosynthesis through the accumulation of cellular folate such as 5-methyltetrahydrofolate (5-MTHF). The accumulation of 5-MTHF, referred to as a "methyl trap," results because the MTHFR reaction is essentially irreversible, and methionine synthase is the only enzyme that can regenerate tetrahydrofolate from 5-MTHF [47],[48]. [0039] Deoxyribonucleoside is a single unit of DNA. Unlike DNA, RNA does not require thymidine. Mammals have four deoxyribonucleoside kinases, deoxycytidine kinase, thymidine kinase 1 and 2 and deoxyguanosine kinase. These two enzyme families phosphorylate deoxyribonucleosides and catalyse the same reaction, and are the precursors for nucleic acid synthesis [49]. [0040] Deficient enzymatic activity of the mitochondrial deoxyribonucleoside kinases deoxyguanosine kinase or thymidine kinase cause mtDNA-depletion syndromes in humans and can produce structural changes in mitochondria, specifically distorted cristae[49]. In addition, mtDNA is essential for intra mitochondrial deoxyribonucleoside phosphorylation to generate pyrimidine 9 deoxynucleotide triphosphates for mtDNA replication[49],[50]. [0041] Folate deficiency has been well documented in the implication of cancer, due to folate's role in DNA structure, stability and transcriptional regulation. This includes the increased susceptibility of DNA to strand breaks, uracil misincorporation, hypomethylation and chromosomal instability[50]. Low thymidine leads to increased incorporation of uracil into DNA, resulting in thymidylate using the folate substrate 5,10-methlenetretrahydrofolate [51]. [0042] Thymidylate synthesis is folate dependent and is also required for DNA synthesis. The critical pathways leading to thymidine, purine, and methionine biosynthesis is likely to limit thymidylate synthesis under conditions of low dietary intake of folate[52]. [0043] DNA methylation is a key regulatory mediator in gene expression, and alterations in histone acetylation and methylation are a common hallmark of cancer. Epigenetic modifications, thus structural changes of the chromatin, influence gene expression. Genes are switched off when the chromatin is closed (heterochromatin), and they are switched on and expressed when the chromatin is open (euchromatin)[44]. [0044] Epigenetic modifications in neurons have neurodegenerative consequences. Histone modifications have been impaired in a broad neurological processes such as post-traumatic stress disorder, memory formation, Parkinson's disease, motor neuron disease, Multiple Sclerosis, stroke and cerebral palsy [53]. [0045] Hypomethylation, folate deficiency and elevated homocysteine has also been implicated in cognitive impairment generally, and in a wide range of neurological conditions [53]. [0046] With an overwhelming body of evidence showing a protective effect of periconceptional folic acid supplementation against neural tube defects led to mandatory folic acid fortification in many countries including the United States and Australia. Folic acid (pteroylmonoglutamic acid) is the synthetic form of folate added to foods and is also found in dietary supplements. Folates are cofactors for biological methylation and nucleic acid synthesis and function as regulatory molecules [54]. [0047] For the metabolism of folate to be able to cross biological membranes, is dependent on several transport systems to enter cells, 10 predominantly by the reduced folate carrier (RFC1). Increased intake of folic acid such as through supplementation, can lead to elevated blood concentrations of unmetabolised folic acid, which can result in altered methylation patterns [54]. [0048] Whilst folic acid and naturally occurring folates are considered to be the same, and the terms are used interchangeably, they are not. Folic acid is the fully oxidized monoglutamyl form of this vitamin and is used commercially in supplements and in fortified foods. The expanding role of folate in health and disease has major health implications [55]. Folate from dietary sources in itsoxidised state contain only one conjugated glutamate residue, folates however are a reduced form as tetrahydrofolates, and are mainly polyglutamated. [0049] Folic acid has a substantially higher bioavailability than naturally occurring folates, and therefore rapidly absorbed across the intestine[54]. The liver is the initial site of folic acid metabolism and this may have important implications for its use as a supplement since humans have a reduced dihydrofolate reductase activity, resulting in a poor ability to reduce folic acid. This may eventually saturate the liver and folate-monoglutamate pool, resulting in significant and potentially dangerous unmetabolised folic acid[56]. [0050] Folic acid has the potential to interfere with the metabolism and regulatory functions of naturally occurring folates as the folate receptor has a higher affinity for folic acid than for 5-MTHF. Further, when in the reduced form, they both compete for enzymes, carrier and binding proteins [54]. Folic acid has been shown to facilitate as well as inhibit DNA synthesis by entering the folate cycle outside normal pathways. Dihydrofolate is a potent inhibitor of MTHFR, which can lead to a decrease in methionine synthesis [57]. [0051] Folate is essential for DNA synthesis and repair. In cancer cells, DNA replication and cell division occur at a rapid rate, therefore higher doses of folic acid could accelerate tumor growth and proliferation. Further, low folate status impairs one carbon-metabolism and DNA methylation which is associated with DNA strand breaks, impaired DNA repair, increased mutations and aberrant and altered DNA methylation patterns[46]. [0052] One-carbon metabolism is cyclical and is regenerated via dietary micronutrients. Ultimately, DNA methylation patterns and dietary practices, 11 particularly micronutrient intake may influence disease phenotypes [46]. Anti folates, such as methotrexate (block folate), are used in cancer treatment. Using a meta-analysis weighted for the duration of folic acid (pteroylglutamic acid) supplementation, studies have demonstrated that cancer incidence of six previously published large prospective folic acid-supplementation trials in men and women, and showed that cancer incidences were higher in the folic acid supplemented groups than the non-folic acid-supplemented groups [58]. [0053] Folate intake is associated with reduced cancer incidence because of the role of folate coenzymes in purine biosynthesis and thymidyate synthesis. Increased pools of purine and thymidine nucleotises could be utilized to repair DNA damage before the initiation of cancer. [0054] Studies have demonstrated that folic acid supplementation may increase cancer incidence,[58] reasons being that increased supply of nucleotides required for replication of mutated cells could stimulate formation of cancer. Studies have clearly demonstrated that there are pro-carcinogenic effects associated with folic acid supplementation[54, 57]. Therefore any reference to folate in the invention only refers to folinic acid and 5 methlytetrahydrofolate (5-MTHF), and should not be replaced or substituted with folic acid. SUMMARY OF THE INVENTION [0055] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. Compounds of the invention are included in the pharmaceutical compositions and used in the methods of the invention. [0056] By the term "treating" and derivatives thereof as used herein, is 12 meant prophylactic and therapeutic therapy. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen. As used herein, the term "effective amount" and derivatives thereof means that amount of a drug, pro-drug, pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" and derivatives thereof means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. [0057] The term also includes within its scope amounts effective to enhance normal physiological function. The pharmaceutically acceptable salts of the compounds of the invention are readily prepared by those of skill in the art by the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of an P13/AKT inhibiting compound, as described herein, and a further active ingredient or ingredients useful in the treatment of cancer, insulin resistance, diabetes, obesity, inflammation, epilepsy, arthritis, neuronal conditions and diseases. [0058] The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment of cancer, insulin resistance, diabetes, inflammation, autoimmune diseases, arthritis, obesity, neurological conditions and diseases. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. [0059] Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered intravenously and another compound may be administered orally. Further, one part of the compound and invention may be administered in a solution or liquid administered orally, and another part administered by a capsule or tablet form administered orally. 13 [0060] Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase 11 inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors. [0061] Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over expression or mutation, has been shown to result in uncontrolled cell growth. [0062] Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Because the pharmaceutically active compounds of the present invention are active as AKT inhibitors they exhibit therapeutic utility in treating cancer, epilepsy, insulin resistance, diabetes, inflammation, arthritis, neurological conditions and diseases (such as all forms of Dementia, ADHD, Epilepsy). Conditions or diseases that can be 14 treated in accordance with this present invention include proliferative diseases (such as cancer), inflammatory disorders, immuno-modulatory disorders, excessive angiogenesis conditions, ischemic disorders, allergy, obesity, autoimmune disorders (such as rheumatoid arthritis and multiple sclerosis). Angiogenesis related conditions and disorders can be treated with this invention in combination with drug combinations with this present invention. [0063] Any cancer or tumor can be treated. Suitably, the present invention relates to a method for treating or lessening the, severity of a cancer selected from: brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden Disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, medulloblastoma, Suitably, the present invention relates to a method for treating or lessening the severity of a cancer such as breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, thyroid, giant cell tumor of bone, thyroid, Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, multiple myeloma, egakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, gastric cancer, nasopharyngeal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular, renal cancer. [0064] The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients to be placed in a solution such as a drink, as 15 appropriate, to give the desired oral or parenteral products. The most preferable and appropriate solvent to be used for the invention is water. [0065] The method of this invention of inducing Akt inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective Akt inhibiting amount of a pharmaceutically active compounds of the present invention. [0066] The invention also provides for a pharmaceutical composition for use as an Akt inhibitor, which comprises a compound of the invention and a pharmaceutically acceptable carrier. [0067] No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention. [0068] In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with an Akt inhibitor. The compounds of this invention may be used alone or in combination with other drugs and therapies used in the treatment of the disease states. [0069] Although the invention has been described with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example, and that changes in the combinations and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of the invention, as hereinafter claimed. [0070] The compounds of the present invention may be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described herein, below. [0071] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. As an inhibitor of the P13/Akt/mTOR signaling pathway, is a 16 compound that inhibits one or more of the aforementioned transduction cascade. While such compounds may be referred to as pathway inhibitors, the present invention includes the use of one of these inhibitors to treat any of the mentioned conditions or diseases regardless of the mechanism of action or how the therapeutic effect is achieved. It is recognized that the invention may have more than one target. The description of the compound as a pathway or protein target (IRS, Akt, mTOR) regulator and inhibitor indicates that a compound possesses such activity, but in no way restricts a compound to having the activity when used as a therapeutic or prophylactic agent. [0072] The invention also provides a pharmaceutical composition for the treatment of the invention for the treatment of hyperproliferative disorders in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or hydrate thereof, and a pharmaceutically acceptable carrier. [0073] The pharmaceutical compositions of the invention may also be in the form of oil in-water emulsions. The oily phase may be a fish oil or a vegetable oil, such as olive oil. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose, and may also contain a demulcent, preservative, flavoring and/or colouring agent. [0074] Although the invention has been described with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example, and that changes in the combinations and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of the invention, as hereinafter claimed. [0075] The compounds of the present invention may be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the 17 present invention can be synthesized using the methods described below, or variations thereon as appreciated by those skilled in the art. Preferred methods and the dose is not restricted, whilst included, but are not limited to, those described herein, described below. [0076] The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use as an Akt inhibitor. [0077] The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in therapy. [0078] The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating cancer. [0079] The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating neurological conditions and diseases. [0080] The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating insulin resistance and diabetes. [0081] The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating arthritis. [0082] The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating inflammation. [0083] The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating obesity. [0084] The invention also relates to pharmaceutical compositions comprising an effective amount of an agent selected from compounds of Formula (I). Methods of making the compounds of Formula (I) are also described. [0085] The present invention provides methods of inhibiting the activity of AKT 18 protein kinases utilizing compounds of Formula (I). [0086] The invention also relates to pharmaceutical compositions comprising an effective amount of an agent selected from compounds of Formula (II). Methods of making the compounds of Formula (II) are also described. [0087] The present invention provides methods of inhibiting the activity of AKT protein kinases utilizing compounds of Formula (II). [0088] The invention also relates to pharmaceutical compositions comprising an effective amount of an agent selected from compounds of Formula (Ill). Methods of making the compounds of Formula (Ill) are also described. [0089] The present invention provides methods of inhibiting the activity of AKT protein kinases utilizing compounds of Formula (Ill). [0090] The amount of a compound of this invention that is combined with one or more other compounds and excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. [0091] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. Solution to the Problem [0092] The compound and invention demonstrates the Akt Inhibiting effects of the invention. Numerous long term studies have clearly demonstrated the Akt Kinase inhibiting ability of raising extracellular pH through alkalyzing minerals and agents such as NaCHO 3 . Since both intracellular and extracellular pH are altered in malignancy, manipulation of tumor pH provides a therapeutic strategy, and can be achieved through the use of alkalizing minerals and agents such NaCHO 3 [22],[59, 60]. [0093] Maintenance of acid-base homeostasis is critical. However, this balance in solid tumors is vulnerable. One of the consequences of increased glucose production 19 is lactate and H+[61]. Whilst tumor cells maintain a normal alkaline intracellular pH, the extracellular pH of malignant solid tumors is acidic, in the range of 6.5 to 6.9, where as the pH of normal tissues is more alkaline, 7.2 to 7.5 [62]. [0094] Numerous vitro and In vivo studies demonstrate the Akt inhibiting effects by raising extracellular pH through oral administration of NaCHO 3 , and that by neutralizing the acid pH of tumors will inhibit invasion and hence reduce spontaneous metastases in a variety of cancers including prostate and breast cancer. Oral administration of alkalyzing agents such as NaHCO 3 has shown to reverse pH of gradients in tumors and not affect the pH of normal tissues [61-63]. By boosting the bicarbonate levels of plasma can elevate the subnormal pH of tumors without influencing the pH of blood or healthy tissues [64]. [0095] Studies have shown that it is possible to raise cellular pH, and therefore increasing 02, demonstrating the Akt inhibiting effects by inhibiting glycolysis, which has been shown to slow the formation of metastases, but at the same time had no effect on blood chemistries indicating that systemic pH was fully compensated. Studies have shown that NaCHO 3 therapy did not result in systemic metabolic alkalosis, further demonstrating that in higher doses is safe and effective at raising pH[63]. By raising the intracellular pH of tumour cells; inhibits glucose uptake (glycolysis), allowing oxygen into the cell. [0096] The glycolytic pathway can be further successfully inhibited through targeted therapy by raising blood ketones, which limits glucose availability, consequently slowing cancer progression [65],[66],[67],[68],[69],[70],[71],[72]. Ketone supplementation has been shown to increase intracellular glucose in the first half of the glycolytic pathway from 2 to 8 fold, but provides a net decrease in the rate of glycolysis, clearly demonstrating the Akt inhibitory effect of ketone ester supplementation[73]. [0097] The large categories of disease for which ketones may provide therapeutic effects includes diseases resulting from free radical damage, hypoxia and insulin resistance[73]. The primary mechanism of action is that ketone bodies inhibit glycolysis, thus decreasing the main pathway of energy production for cancer cells [74], [75]. [0098] Ketone supplementation such as acetoacetate and b-hydroxybutyrate have been shown to decrease viability and increase apoptosis in cancer cells, but had no effect on fibroblasts [68]. Ketone esters can readily increase blood levels of ketone 20 bodies, providing a novel approach as an Akt Inhibitor, limiting energy substrates in cancer cells [76], [77]. [0099] Raising blood ketones produce a physiological metabolic shift to an environment unfavourable to cancer cells due to decreased circulating blood glucose which limits energy substrates, demonstrating anticancer affects. Acetoacetate and b hydroxybutyrate are the two most abundant and relevant of the three ketone bodies. Studies have shown that Acetoacetate supplementation provides positive effects by inhibiting proliferation and ATP production in many different types of aggressive human cancers including colon and breast cancer cell lines but did not affect proliferation in healthy primary fibroblasts [78]. [0100] Ketones reduce ATP production and tumor size in vitro in all experiments[78]. It was demonstrated that by increasing blood ketones inhibited disease progression and promoted partial remission in patients with advanced metastatic cancers from various tissue origins [72]. [0101] Treatment methods using therapeutic hypoglycaemia has the ability to rapidly induce tumor cell necrosis [11], [79]. [0102] In addition, cancer cells thrive in an environment of elevated ROS production, but are very sensitive to even small changes in redox status. Importantly, Ketones decrease mitochondrial ROS production and enhance endogenous antioxidant defences in normal cells [80], but not in cancer cells [76]. [0103] Ketone bodies are transported into the cell through the monocarboxylate transporters (MCTs), which are also responsible for lactate export. It has been shown that inhibiting MCT1 activity through lactate export from the cell dramatically decreases cancer cell growth and survival, demonstrating Akt inhibiting affects [81]. [0104] Further studies have demonstrated the Akt inhibiting effects of b hydroxybutyrate which acts as an endogenous HDAC inhibitor which is easily achieved through ketone supplementation such as a ketone ester [82]. [0105] It is possible to raise blood ketone levels without the need for carbohydrate restriction by administering a source of supplemental ketones such as ketone esters. Evidence shows that ketone bodies can inhibit cancer progression independently of other factors such as carbohydrate restriction or calorie restriction [78], [83]. 1,3 Butanediol is a pro-drug and hypoglycemic agent that is converted to b hydroxybutyrate by the liver [84], [85]. [0106] Insulin and catecholamines (stress hormones) regulate key metabolic 21 enzymes. Insulin is an anabolic hormone, causing cells to take up energy substrates at times of excess. Stable blood glucose levels are essential to life, and are held within very narrow limits. Glucose uptake to muscle and fat cells is dependent upon activation of the glucose transporters by insulin, which signals food abundance and initiates uptake and storage of carbohydrates, fats and amino acids. Insulin is countered by the catabolic hormones glucagon, adrenalin, noradrenalin and growth hormone. [0107] When the insulin system fails either through the destruction of Islet beta cells (type 1 diabetes) or the loss of a response to insulin (type 2 diabetes/insulin resistance), the liver activates gluconeogenesis, releasing sugar in spite of elevated blood glucose levels. [0108] Mild ketosis is a normal physiological response to decrease blood glucose levels. Studies on the effects of insulin and ketone bodies in the perfused working heart suggest that ketosis, within limits, mimics the effects of insulin. Ketone bodies increase intracellular glucose by providing alternative metabolic substrates that increase mitochondrial acetyl CoA[73]. Insulin acts on energy production by activating pyruvate dehydrogenase (PDH). Both insulin and ketones have the same effects on the metabolites of the first third of the TCA cycle on mitochondrial redox states. [0109] Ketone body derived acetyl CoA enters the pathway to the krebs cycle, activating pyruvate dehydrogenase, bypassing blocks in glucose utilisation. Inhibition of PDH activity caused by insulin resistance can be overcome by increase blood ketones. [0110] One particular study compared the effects of physiologic levels of ketones to the metabolic and physiologic effects of insulin, demonstrating that the acute metabolic effects of insulin were qualitatively duplicated by the addition of 4mM B hydroxybutryate and 1mM Acetoacetate, that the increase in the efficiency was the same as with the addition of insulin [86]. [0111] The physiological effect of Ketone esters to correct most of the metabolic defects of acute insulin deficiency provides a therapeutic role of ketone bodies during periods of impaired insulin resistance [86]. [0112] Radiation and chemotherapy are effective largely by the induction of ROS in the tumor, but at the same time incur damage to normal tissue. Ketone metabolism would mitigate some of the adverse side effects and therefore protect against oxidative stress. 22 [0113] The Warburg effect is the most ubiquitous cancer phenotype, exhibited by most if not all cancer types, and has long been accepted, especially prevalent in aggressive cancers and metastatic cells. Metastasis is the primary cause of cancer morbidity and mortality and is responsible for more than 90% of all cancer related deaths [87]. Using novel and innovative methods to treat cancer at the source by inhibiting the Akt pathway that shunts metabolism towards glycolysis, provides a novel and effective method of cancer treatment. The invention combines novel pharmaceutical ingredients that when combined provide a powerful synergistic effect, by inhibiting the glycolytic pathway on a number of targets. [0114] The table shows the concentrations typically seen under different conditions: blood concentration (millimolar) Condition <0.2 not in ketosis 02-05 slight/mild ketosis 0.5 - 3.0 induced ketosis *Highlighted, ketone supplementation would initiate a state of induced ketosis THE INVENTION FORMULA (I) [0115] The compounds detailed in the table Formula (I) is to be mixed into a viscous solution to be consumed as a flavoured drink such as strawberry or vanilla (the vehicle). The formula (I) relates to the compound as stated in the table below. Sodium bicarbonate - NaCHO 3 *Na-O OH 0 Beta-hydroxybutyrate 23 OH O H3C ' OH L-selenomethionine Se 0

H

2 N OH Potassium iodide Zinc picolinate Potassium gluconate OH OH 0' K OH OH 24 Magnesium chloride Calcium aspartate C a Methylsulfonylmethane (MSM) O 1) || HC -S

CH

3 || 00 M ethyltetrahyd rofo late (5-MTHF) 25 Folinic acid

HN-

N HNa Methylcobalamin Pyridoxal-5-phosphate HO N'N H Thiamine 26

NH

2 N Ns

H

3 C N H 3 C OH Riboflavin C* HH, HO H N > OH N H OH H OH N O N O' H Nicotinic acid 0 OH N Pantothenic acid 3 C C0 HO OH Sodium ascorbate 27 HOH HO O Na* -O OH Cholecalciferol Alpha Lipoic acid L-Cysteine - amino acid 0 OH H 2N

-

J O H SH L-Tyrosine - amino acid 28 OH

NH

2 HOO 29 Formula (I) - Combined Therapy Single Dose / 200ml Ketone Esters is a pro-drug specifically - 6gm Beta-hydroxybutyrate NaCHO 3 -sodium salt, sodium bicarbonate 2g Selenium - (as L-selenomethionine) 25ug Iodine - (as potassium iodide) Iodine - (as potassium iodide) Zinc (as zinc picolinate) 10mg Potassium (as potassium gluconate) 1000mg Magnesium (as magnesium chloride or citrate) 500mg Calcium (as calcium aspartate) 300mg Organic Sulphur (99% Methylsulfonylmethane 2gm (MSM) and under 0.5% Moisture) Methylfolate - (as methyltetrahydrofolate (5-MTHF) 25ug B9 - (as Folinic acid) 200ug B12 -(as Methylcobalamin) 500ug B6 - (as Pyridoxal-5-phosphate) 10mg B1 - (as Thiamine) 5mg B2 - (as Riboflavin) 5mg B3 - (as Nicotinic acid) 10mg B5 - (as Pantothenic acid) 5mg Vitamin C (as Sodium ascorbate) 500mg Vitamin D3 (as Cholecalciferol) 1,000lUs R-Alpha Lipoic acid 100mg L-Cysteine - amino acid 500mg L-Tyrosine - amino acid 500mg FORMULA (II) [0116] The compound detailed in the table Formula (II) is to be mixed into a viscous solution to be consumed as a flavoured drink such as strawberry or vanilla (the vehicle). The formula (II) relates to the compound as stated in the table below. Sodium bicarbonate - NaCHO 3 *Na-O OH 0 Beta-hydroxybutyrate 30 OH O H3C ' OH L-selenomethionine Se 0

H

2 N OH Potassium iodide Zinc picolinate Potassium gluconate OHQOH K, HO, OH OH 31 Magnesium chloride Calcium aspartate O )a

NH

2 O Organic Sulphur (99% Methylsulfonylmethane (MSM) 0 I I H3C -S-CH 3 I I Thiamine

NH

2 N S

H

3 C N H 3 C OH 32 Formula (II) - Combined Therapy Single Dose / 200ml Ketone Esters is a pro-drug specifically - 6gm Beta-hydroxybutyrate NaCHO 3 -sodium salt, sodium bicarbonate 2g Selenium - (as L-selenomethionine) 25ug Iodine - (as potassium iodide) Iodine - (as potassium iodide) Zinc (as zinc picolinate) 10mg Potassium (as potassium gluconate) 1000mg Magnesium (as magnesium chloride or citrate) 500mg Calcium (as calcium aspartate) 200mg Organic Sulphur (99% Methylsulfonylmethane 2gm (MSM) and under 0.5% Moisture) B1 - (as Thiamine) 5mg FORMULA (111) [0117] The compound detailed in the table Formula (Ill) is to be mixed into a viscous solution to be consumed as a flavoured drink such as strawberry or vanilla (the vehicle). The formula (Ill) relates to the compound as stated in the table below. Sodium bicarbonate - NaCHO 3 *Na-O OH 0 Beta-hydroxybutyrate OH O

H

3 C' OH L-selenomethionine 33 Se 0

H

2 N OH Potassium iodide Zinc picolinate NN Potassium gluconate OH OH O" K t HON OH OH Magnesium chloride 34 Calcium aspartate Methylsulfonylmethane (MSM) O 1) || H C S CH 3 || 00 M ethyltetrahyd rofo late (5-MTHF) Folinic acid HQ

HN--

.. ... . ... H NN N -OH 35 Methylcobalamin #M Pyridoxal-5-phosphate CH Thiamine NH2 N N H3C N H3C OH 36 Riboflavin CH, HIC Y Y N OI- H N H OH H H N J1 O N a H Nicotinic acid 0 Pantothenic acid HO , O HOH H Sodium ascorbate HOH HOH HO O Na* -O OH Cholecalciferol 37 L-Cysteine - amino acid OH H 2N

-

J O H SH L-Tyrosine - amino acid HO L-Tryptophan - amino acid NOH N H 38 Formula (Ill) - Combined Therapy Single Dose / 200ml Ketone Esters is a pro-drug specifically - 6gm Beta-hydroxybutyrate NaCHO 3 -sodium salt, sodium bicarbonate 1g Selenium - (as L-selenomethionine) 25ug Iodine - (as potassium iodide) 1mg Zinc (as zinc picolinate) 10mg Potassium (as potassium gluconate) 1000mg Magnesium (as magnesium chloride or citrate) 500mg Calcium (as calcium aspartate) 200mg Organic Sulphur (99% Methylsulfonylmethane 2gm (MSM) and under 0.5% Moisture) Methylfolate - (as methyltetrahydrofolate (5-MTHF) 25ug B9 - (as Folinic acid) 200ug B12 -(as Methylcobalamin) 500ug B6 - (as Pyridoxal-5-phosphate) 10mg B1 - (as Thiamine) 5mg B2 - (as Riboflavin) 5mg B3 - (as Nicotinic acid) 10mg B5 - (as Pantothenic acid) 5mg Vitamin C (as Sodium ascorbate) 200mg Vitamin D3 (as Cholecalciferol) 500lUs L-Cysteine - amino acid 500mg L-Tyrosine - amino acid 500mg L-Tryptophan - amino acid 500mg [0118] While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved. 39 References: also provided in the "Description of Embodiment" document. 1 . 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Claims (25)

1. 5-Methyltetrahydrofolate (5-MTHF) 0 OH 0 OH S N H I HZ N O0O H2N N H H Folinic acid 0 HN jO 0, H /N N OH N HN HN HN HO Methylcobalamin 0 H2NNH 2 H3C \ C+/ NH 0H NH N H CH N NH C 00 HO Pyridoxal-5-phosphate 0 C-H 0 HO CH 2 0-P-OH H 3 C N 4 Thiamine NH 2 N t> H 3 C N H 3 C OH Riboflavin CH 3 H 3 C O H 3C HO H N OH N H OH H OH N O N O H Nicotinic acid 0 (lk .OH N Pantothenic acid 5 HaC CH3 O O HO OH H OH Sodium ascorbate HOH 1: H 0 HOO HO O Na' -O OH Cholecalciferol H3C,,, CH3 CH 3 H H 3 CH 2 HO" Alpha Lipoic acid 0 OH S-s 6 L-Cysteine - amino acid 0 H 2 N OH SH L-Tyrosine - amino acid 0 HOOH CLAIM 2. A compound according to Formula (11): Sodium bicarbonate - NaCHO 3 *Na-O OH 0 7 Beta-hyd roxybutyrate L-selenomethionine Se 0 H 2 N OH Potassium iodide 0 0 0 N aNO N KI I HGI NH2 N.6c Zinc picolinate 0N0 8 Potassium gluconate Magnesium chloride CF 3 C -Mg Calcium aspartate 0 NH 2 O Organic Sulphur (99% Methylsulfonylmethane (MSM) 0 H 3 C- S -CH3 0 9 Thiamine NH 2 N s I -~ S H 3 C N H 3 C OH CLAIM 3. A compound according to Formula (111): Sodium bicarbonate - NaCHO 3 *Na-O OH 0 Beta-hyd roxybutyrate L-selenomethionine 10 Se 0 H 2 N OH Potassium iodide 0 0 0 N NaN0~t KI + NH 2 D-5 .C N Zinc picolinate N IN Potassium gluconate 11 Magnesium chloride CF 3 Ci -Mg Calcium aspartate 0 0- Ca ++ NHz O Methylsulfonylmethane (MSM) 0 || H3C-- S--CH3 5-Methyltetrahydrofolate (5-MTHF) 12 0 OH 0 O OH NNO O H H H N0 N Ne ri H H 2 N N N H H Folinic acid 0 HN 0 H 2 N-ix N OH N HN HN HN HO Methylcobalamin 13 00 H2N NH CH NH2 H CH 3 CHI NH $raCHI N1 : CH3 0/ OHI HO Pyridoxal1-5-p hos phate 0 C-H 0 HO CH 2 O-P-OH H 3 C 6 N Thiamine NH 2 N ~ H 3 C N H 3 C OH Riboflavin 14 CH 3 H 3 C O H 3C HO H N OH N H OH H OH N O N O H Nicotinic acid O Iyk OH N Pantothenic acid H 3 C CH 3 0 O HO OH H OH Sodium ascorbate HO .0 HO O Na* -0 OH 15 Cholecalciferol H 3 C,, CH 3 CH 3 H CH2 HO" L-Cysteine - amino acid 0 OH H 2 N O H SH L-Tyrosine - amino acid 0 OH NH 2 HOD 16 L-Tryptophan - amino acid For example: 1. The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, or tablet forms, or mixing, filling and dissolving the ingredients to be placed in a solution such as a drink, as appropriate, to give the desired oral or parenteral products. 2. The method of this invention of inducing Akt inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective Akt inhibiting amount of a pharmaceutically active compounds of the present invention. 3. The invention also provides for a pharmaceutical composition for use as an Akt inhibitor, which comprises a compound of the invention and a pharmaceutically acceptable carrier. 4. The invention provides a pharmaceutical composition for the treatment of the invention for the treatment of hyperproliferative disorders such as cancer in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or hydrate thereof, and a pharmaceutically acceptable carrier. 5. The pharmaceutical compositions of the invention may also be in the form of oil in-water emulsions. The oily phase may be a fish oil or a vegetable oil, such as olive oil. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or, naturally occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids. The emulsions 17 may also contain sweetening, flavoring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, sorbitol or sucrose, and may also contain a demulcent, preservative, flavoring and/or colouring agent.
2. 6. The compounds of the present invention may be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using various methods, or variations thereon as appreciated by those skilled in the art.
3. 7. The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use as an Akt inhibitor.
4. 8. The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in therapy.
5. 9. The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating cancer.
6. 10. The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating neurological conditions and diseases.
7. 11. The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating insulin resistance and diabetes.
8. 12. The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating arthritis.
9. 13. The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating inflammation.
10. 14. The invention also provides for the use of a compound of the invention in the manufacture of a medicament for use in treating obesity.
11. 15. The invention also relates to pharmaceutical compositions comprising an effective amount of an agent selected from compounds of Formula (1).
12. 16.
13. 17. The invention also relates to pharmaceutical compositions comprising an effective amount of an agent selected from compounds of Formula (11).
14. 18. The invention also relates to pharmaceutical compositions comprising an effective amount of an agent selected from compounds of Formula (111).
15. 19. The amount of a compound of this invention that is combined with one or more other compounds and excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. 18
16. 20. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a compound of any one of the previous claims.
17. 21. The compound of any one of the claims 1 to 3 to be used as a therapy.
18. 22. The compound of any one of the claims 1 to 3 for use in the prevention or treatment of cancer.
19. 23. The compound of any one of the claims 1 to 3 for use in the prevention or treatment of insulin resistance or diabetes.
20. 24. The compound of any one of the claims 1 to 3 for use in the prevention or treatment of arthritis.
21. 25. The compound of any one of the claims 1 to 3 for use in the prevention or treatment of neuronal conditions and diseases.
22. 26. The compound of any one of the claims 1 to 3 for use in the prevention or treatment of epilepsy.
23. 27. The compound of any one of the claims 1 to 3 for use in the prevention or treatment of inflammation.
24. 28. The compounds of the present invention may be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using various methods, or variations thereon as appreciated by those skilled in the art.
25. 29. A method of preventing or treating cancer or the stated conditions and diseases, comprising administering a compound according to any one of the claims 1 to 3 to a subject in thereof, optionally with other treatments. 19