INOSITOL PHOSPHATE COMPOUNDS FOR USE IN THE TREATMENT, INHIBITION OF PROGRESSION, OR PREVENTION OF CARDIOVASCULAR CALCIFICATION

Abstract

The present invention relates to compounds, pharmaceutical compositions, combination preparations, and dosage guidelines for the treatment, inhibition of progression, and prevention of cardiovascular calcification, and in particular, coronary calcification, aortic artery calcification, and aortic valve calcification, comprising inositol phosphates. In one particular aspect, the disclosure provides a dosage guideline for the treatment, inhibition of progression, or prevention of cardiovascular calcification comprising the administration of approximately 200 mg to approximately 700 mg of myo-inositol hexaphosphate per dose.

Description

INOSITOL PHOSPHATE COMPOUNDS FOR USE IN THE TREATMENT, INHIBITION OF PROGRESSION, OR PREVENTION OF CARDIOVASCULAR CALCIFICATION Field of invention The present invention relates to the use of inositol phosphates (IPs), their analogues, and derivatives for the treatment, inhibition of progression, or prevention of cardiovascular calcification in human health. The present invention also relates to pharmaceutical compositions and combination preparations comprising said IPs and a dosage regimen for their administration. Background of the technique The relative risk of death from cardiovascular causes is 5 to 30 times higher in patients with end-stage renal disease (ESRD) requiring dialysis than in the general population (Foley R, et al., Am J Kidney Dis. 1998; 32:3112-119). Although traditional risk factors, such as diabetes mellitus and hypertension, are highly prevalent in patients with chronic kidney disease (CKD), these represent only a part of the increased cardiovascular risk (Cozzolino M, et al., Nephrol Dial Transplant. 2018; 33:iii28-iii34). In clinical practice, at least 80% of patients receiving maintenance hemodialysis have signs of cardiovascular calcification (Raggi P, et al., J Am Coll Cardiol. 2002;39: 695-701 and Bellas A, et al., Kidney Int. 2006; 70:1623-1628). This marker of vasculopathy has been associated with morbidity and mortality in the general population and in patients receiving maintenance hemodialysis (Blaha M, et al.)., Lancet 2011; 378:684-6 y Chen J, et al., JAMA Cardiol. 2017; 2:635-643). In patients with advanced CKD, cardiovascular calcification is likely secondary to a combination of accelerated atherosclerosis and, more likely, to arteriosclerosis related to mineral metabolism disorders (Johnson R, et al., Circ Res. 2006; 99:1044-1059 and Raggi P, et al., Nat Clin Pract Cardiovasc Med. 2007; 4:26-33). Cardiovascular calcification is a highly regulated process that resembles ossification and ultimately depends on PAH nucleation and crystal growth. Patients with CKD and cardiovascular calcification have increased morbidity and mortality through several pathways, including coronary atherosclerosis, arterial stiffness, left ventricular hypertrophy, myocardial ischemia, and electrocardiographic abnormalities. (Brown A, et al., Nat Rev Cardiol. 2016; 13:210220, Raggi P, et al., Kidney Int. 2007;71:802-807, Di lorio B, et al., Kidney Blood Press Res. 2011; 34:180-187, Kitamura K, et al., Heart Vessels. 2017; 32:1109-1116 and Karohl C, et al., J Nucí Cardiol. 2013; 20:1013-1020). There is evidence that slowing the progression of vascular calcification in chronic kidney disease (CKD) is associated with reduced mortality (Jamal S, et al., Lancet 2013; 382:1268-1277). The phosphate binder sevelamer and the calcimimetic cinacalcet, used to treat hyperphosphatemia and secondary hyperparathyroidism, respectively, can slow the progression of vascular calcification in end-stage renal disease (ESRD). However, these drugs do not fully address the complex biology responsible for vascular calcification (Patel L, et al., Clin J Am Soc Nephrol. 2016; 11:232-244 and Raggi P, et al., Nephrol Dial Transplant. 2011; 26:1327-1339). SNF472, a myo-inositol hexaphosphate formulation, acts through a novel pathway to selectively and directly inhibit the formation and growth of PAH crystals, the final stage frequently involved in the pathophysiology of vascular calcification (Ferrer M, et al., Sci Rep. 2017; 7:6858 and Ferrer M, et al., PLoS ONE 2018; 13:e0197061). Infusion of SNF472 during each dialysis session achieves therapeutic levels, ensuring adherence to treatment without additional burden for the patient (Perelló J, et al., J Nephrol. 2018;31:287-296). A phase 1 clinical trial showed that, in patients receiving maintenance hemodialysis, administration of a single dose of SNF472 at 9 mg / kg inhibited the PAH crystallization potential by 80%, compared to 9% with placebo (Perelló J, et al., Br J Clin Pharmacol. 2018; 84:28672876).Therefore, SNF472 could be a product with therapeutic potential for attenuating the progression of cardiovascular calcification in patients undergoing dialysis. Summary of the invention In one aspect, the present invention relates to a compound of General Formula I or a pharmaceutically acceptable salt thereof: where: (i) Ri, R3, R5, R7, Rg and R11 are independently selected from OH, a radical of Formula II, III, IV and a heterologous moiety: II III IV (ii) at least one of Ri, R3, Rs, R?, Rg and Rn is selected from a radical of Formula II, III and IV; and (iii) zero, one, two or three of Ri, R3, Rs, R?, Rg and Rn is a heterologous residue; for use in the treatment, inhibition of progression or prevention of cardiovascular calcification or of a disease, condition or symptom associated with cardiovascular calcification in a subject in need thereof, wherein (a) the compound is in a form suitable for parenteral, topical or enteric administration and (b) the compound is administered to the subject in a non-bolus extended-release form in an effective dosage of approximately 200 mg to approximately 700 mg per administration. In some respects, the present invention relates to a compound of general Formula I, as defined above, wherein the heterologous residue is selected from a radical of Formula V, a radical of Formula VI, and a radical of Formula VII: L 7 Rfrnn / Zznz / E / YIAI VII and where n is an integer in the interval from 2 to 200 and R13 is selected from H, methyl or ethyl. Alternatively, the invention relates to a compound of General Formula I, as defined above, for use in the treatment, inhibition of progression, or prevention of cardiovascular calcification in a subject in need thereof, wherein (a) the compound is in a form suitable for parenteral, topical, or enteric administration, and (b) the compound is administered to the subject in a non-bolus, extended-release form in a dosage of approximately 200 mg to approximately 700 mg per administration, and (c) administration of the compound treats, inhibits progression, or prevents cardiovascular calcification or a disease, condition, or symptom associated with cardiovascular calcification in the subject. In a further aspect, the invention also relates to a method for treating, inhibiting the progression of, or preventing cardiovascular calcification, comprising administering a therapeutically effective amount of a Formula I compound, as defined above, together with pharmaceutically acceptable excipients or carriers, to a subject in need. This aspect can also be formulated as the use of a Formula I compound, as defined above, for the manufacture of a medicament for treating, inhibiting the progression of, or preventing cardiovascular calcification in a subject in need. In another aspect, the invention also relates to a method for treating, inhibiting the progression of, or preventing coronary artery calcification, comprising administering a therapeutically effective amount of a compound of Formula I, as defined above, together with pharmaceutically acceptable excipients or carriers, to a subject in need. This aspect can also be formulated as the use of a compound of Formula I, as defined above, for the manufacture of a medicament for treating, inhibiting the progression of, or preventing coronary artery calcification in a subject in need. In a further aspect, the invention relates to a method for treating, inhibiting the progression of, or preventing aortic calcification, comprising administering a therapeutically effective amount of a compound of Formula I, as defined above, together with pharmaceutically acceptable excipients or carriers, to a subject in need. This aspect can also be formulated as the use of a compound of Formula I, as defined above, for the manufacture of a medicament for treating, inhibiting the progression of, or preventing aortic calcification in a subject in need. In a further aspect, the invention relates to a method for treating, inhibiting the progression of, or preventing aortic valve calcification, comprising administering a therapeutically effective amount of a Formula I compound, as defined above, together with pharmaceutically acceptable excipients or carriers, to a subject in need. This aspect can also be formulated as the use of a Formula I compound, as defined above, for the manufacture of a medicament for treating, inhibiting the progression of, or preventing aortic valve calcification in a subject in need. The compounds of the present invention are particularly useful for the treatment, inhibition of progression or prevention of coronary artery calcification, aortic artery calcification and / or aortic valve calcification in dialysis patients and, in particular, in dialysis patients with renal failure. The invention also provides a pharmaceutical composition comprising at least one Formula I compound, as defined above, for use in: (i) the treatment, inhibition of progression or prevention of cardiovascular calcification, (ii) the treatment, inhibition of progression or prevention of coronary artery calcification, (iii) the treatment, inhibition of progression or prevention of aortic artery calcification and / or (iv) the treatment, inhibition of progression or prevention of aortic valve calcification in a subject in need. In a further aspect, the invention relates to a combined preparation comprising at least one compound of Formula I or a pharmaceutical composition according to the invention and at least one second active agent and to the use of said combined preparation in human health and, in particular, in dialysis patients with renal failure. Brief description of the drawings Figure 1 shows representative inositol phosphate analogues in which two of six X's are OPSO22- and the remaining X's are OSO3. Four specific forms of 4,6-di-(O-thiophosphate)-inositol1,2,3,5-tetra-O-sulfate are shown. Figure 2 shows inositol phosphate analogues and inositol phosphate derivatives that can be used to implement the methods of the present invention. The molecules shown are myo-inositol-pentakisphosphate-2-PEG400, myo-inositol hexakis-sulfate (myo-inositol hexasulfate), and escillo-inositol hexakis-sulfate (escillo-inositol hexasulfate). Figure 3 shows inositol phosphate analogues and inositol phosphate derivatives that can be used to implement the methods of the present invention. The Xs independently represent phosphorus- and / or sulfur-containing groups (e.g., phosphate, sulfate, or thiophosphate). R1 ​​represents a heterologous moiety (e.g., PEG or PG). Figure 4 shows example inositol phosphate analogues and inositol phosphate derivatives that can be used to implement the methods of the present invention. R1 represents a heterologous moiety (e.g., PEG or PG). n can be between 2 and 200. Fig. 5 shows example inositol phosphate analogues and inositol phosphate derivatives that can be used to implement the methods of the present invention, n can be between 2 and 200. Fig. 6 shows example inositol phosphate analogues and inositol phosphate derivatives that can be used to implement the methods of the present invention, n can be between 2 and 200. Figure 7 illustrates the patient allocation in the clinical study. 231 patients did not have a coronary artery calcium score within the required screening range (*). Other reasons for patient exclusion included incomplete or unevaluable computed tomography, kidney transplantation, or closed screening / enrollment (t). Figure 8 shows the mean change (95% CI) from baseline to week 52 in calcium scores in the SNF472 combination dosing groups compared with placebo. Modified intention-to-treat (mITT) population with last observation completed (LOCF). A, coronary artery calcium volume. B, coronary artery Agatston score. C, aortic valve calcium volume. D, aortic valve Agatston score. E, thoracic aortic calcium volume. F, thoracic aortic Agatston score. Figure 9 shows the evolution of calcium volume and Agatston scores obtained in the per-protocol (PP) population of patients who completed 52 weeks of treatment. A, coronary artery calcium volume. B, coronary artery Agatston score. Figure 10 shows the proportion of patients with a change of <15% in the Agatston score of CAC at week 52. A, in the mITT population. B, in the PP population. Figure 11 shows the mean change (95% CI) from baseline to week 52 in calcium scores in the SNF472 combination dosing groups and the single-dose groups compared with placebo. Modified intention-to-treat (mITT) population with one last observation performed (LOCF). A, coronary artery calcium volume. B, coronary artery Agatston score. C, aortic valve calcium volume. D, aortic valve Agatston score. E, thoracic aortic calcium volume. F, thoracic aortic Agatston score. Figure 12 shows the mean sensitivity analysis of the mean change (95% CI) from baseline to week 52 of calcium scores in the SNF472 combination dosing groups compared with placebo. Modified intention-to-treat (mITT) population with multiple imputation methods. A, coronary artery calcium volume score. B, Agatston score of coronary artery calcium. C, aortic valve calcium volume score. D, Agatston score of aortic valve calcium. E, thoracic aortic calcium volume score. F, Agatston score of thoracic aortic calcium. Detailed description of the invention The present invention provides compounds, pharmaceutical compositions, combination preparations, methods, and routes of administration for use in the treatment, inhibition of progression, or prevention of cardiovascular calcification. The invention also provides compounds, pharmaceutical compositions, methods, and routes of administration for use in the treatment, inhibition of progression, or prevention of coronary artery calcification, aortic artery calcification, and / or aortic valve calcification. The compounds, pharmaceutical compositions, combination preparations, methods, and routes of administration of the present invention are particularly useful for the treatment, inhibition of progression, or prevention of coronary artery calcification, aortic artery calcification, and / or aortic valve calcification in dialysis patients, and more specifically, in dialysis patients with renal failure. Definitions of terms and general expressions The present invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. It also includes embodiments in which more than one or all of the members of the group are present in, used in, or otherwise relevant to a given product or process. Unless otherwise defined, all technical and scientific terms and expressions used herein have the same meaning as commonly understood by a person skilled in the art to which this description refers. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Pei-Show J, 2nd ed., (CRC Press, Boca Raton, FL, USA, 2002); The Dictionary of Cell and Molecular Biology, Lackie J, 5th ed., (Academic Press, Cambridge, MA, USA, 2013); and the Oxford Dictionary of Biochemistry and Molecular Biology, Cammack R, et al., 2nd ed., (Oxford University Press, Oxford, GB, 2006) provide a person skilled in the art with a general dictionary of many of the terms and expressions used herein. Units, prefixes, and symbols are stated in their accepted form of the International System of Units (SI). Numerical ranges include the numbers defining the range. When a range of values ​​is cited, it is understood that each intermediate whole value and each fraction thereof, between the cited upper and lower limits of that range, is also specifically disclosed, together with each sub-interval between such values. The upper and lower limits of any range may be included in or excluded from the range independently, and each range in which either, neither, or both limits are included is also covered within the invention. When a value is explicitly stated, it is understood that values ​​that are approximately the same quantity or number as the stated value are also within the scope of the invention. When a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of the invention. Conversely, when different elements or groups of elements are disclosed individually, combinations of those elements are also disclosed. When it is disclosed that any element of an invention has a plurality of alternatives, examples of that invention in which each alternative is excluded, either individually or in any combination with the other alternatives, are also disclosed. More than one element of an invention may have such exclusions, and all combinations of elements having such exclusions are disclosed. The expression "and / or," as used herein, should be understood as the specific disclosure of each of the two specified features or components with or without the other. Therefore, the expression "and / or," as used in an expression such as "A and / or B" herein, is intended to include A and B, A or B, A (alone), and B (alone). Similarly, the expression "and / or," as used in an expression such as "A, B, and / or C," is intended to encompass each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). The term aortic calcification, as used herein, refers to the formation of calcium deposits in the aorta. Types of aortic calcification include, but are not limited to, calcification of the abdominal and thoracic aorta and the external and internal common iliac arteries (e.g., femoral and lateral sacral). The term aortic valve calcification, as used herein, refers to the formation of calcium deposits on the aortic valve. Aortic valve calcification can result in narrowing of the aortic valve, a condition defined as aortic valve stenosis or AVS. Blood flow to the heart can be reduced due to AVS, causing excessive strain and weakness of the myocardium. The term "approximately," as used herein and as applied to one or more values ​​of interest, refers to a value that is similar to a stated reference value. In certain respects, the term "approximately" refers to a range of values ​​that lie within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or less than) of the stated reference value, unless otherwise stated or otherwise evident from the context (except where such a number exceeds 100% of a possible value). The term cardiovascular calcification, as used herein, and its related term CVC refer to the formation of calcium deposits in the blood vessels of the heart. Calcification can occur in the intima (inner) or media (middle layer) of the blood vessel. Types of cardiovascular calcification include, but are not limited to, coronary artery calcification, aortic calcification, and aortic valve calcification.Diseases, conditions and / or symptoms associated with cardiovascular calcification (e.g., coronary artery calcification, aortic artery calcification and aortic valve calcification) include, but are not limited to, angina pectoris, aneurysm, atherosclerosis (e.g., coronary atherosclerosis), arterial stiffness, arteriosclerosis, heart disease, cerebrovascular disease, coronary artery disease, electrocardiographic abnormalities, heart failure, congestive heart failure, hypertension, left ventricular hypertrophy, myocardial infarction, myocardial ischemia, peripheral artery disease, peripheral vascular disease and thrombosis. The term compound, as used herein, is understood to include all isomers and isotopes of the represented structure. As used herein, the term isomer means any isomer, tautomer, dipolar ion, stereoisomer, enantiomer, or geometric diastereomer of a compound. Compounds may include one or more chiral centers and / or double bonds and, therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-) or cs / trans isomers)). The present invention encompasses each and every isomer of the compounds described herein, including stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomeristic pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.Enantiomeric and stereomeric mixtures of compounds and the means for resolving them into their enantiomeric or stereoisomeric components are well known. A compound, salt, or complex of the present invention can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods. The term coronary artery calcification, as used herein, refers to the formation of calcium deposits in the coronary arteries. The term "effective quantity," as used herein, with reference to (i) a compound of General Formula I (for example, an inositol phosphate, an inositol phosphate analogue, an inositol phosphate derivative, or a combination thereof) or (ii) a pharmaceutical composition comprising at least one of the compounds in point (i), is that quantity sufficient to effect the beneficial or desired results. In some embodiments, the beneficial or desired results are, for example, clinical results, and as such, an effective quantity depends on the context in which it is used.In the context of administering an active agent that prevents, inhibits the progression of, or treats cardiovascular calcification, an effective amount of an active agent is, for example, an amount sufficient to (a) inhibit the formation and / or growth of PAH crystals in a specific area of ​​cardiovascular tissue in a subject, (b) slow the progression of the formation and / or growth of PAH crystals in a specific area of ​​cardiovascular tissue in a subject, or (c) reduce, stop, or eliminate the symptoms associated with cardiovascular calcification in a subject who needs it, compared to the same parameters observed in the subject before administration of the active agent or in a population of control subjects without administration of the active agent. The term renal insufficiency, as used herein, refers to a disease that causes a progressive loss of kidney function, with a simultaneous decrease in the glomerular filtration rate (GFR). Renal insufficiency is also known as kidney failure or kidney disease. Kidney disease can be classified as (i) acute kidney injury (AKI), a progressive loss of kidney function, which usually causes oliguria and fluid and electrolyte imbalance, and (ii) chronic kidney disease (CKD), a much slower loss of kidney function over a period of months or years.Depending on the degree of kidney function, five stages of CKD are defined based on GFR: (a) stage 1, normal or high GFR (>90 ml / min), (b) stage 2, mild CKD, GFR=60-89 ml / min, (c) stage 3, moderate CKD, GFR=30-59 ml / min, (d) stage 4, severe CKD, GFR=15-29 ml / min, and (e) stage 5, end-stage CKD, GFR <15 ml / min. In stage 5, dialysis or a kidney transplant is required to maintain health. AKI and CKD can occur simultaneously, which is known as acute-on-acute kidney injury. The term excipient, as used herein, refers to a substance that aids in the absorption of the components of the pharmaceutical composition, stabilizes those components, activates them, or assists in the preparation of the composition. Therefore, examples of excipients used in parenteral formulations include, but are not limited to, antimicrobial agents (e.g., benzalkonium chloride, metacresol, and thimerosal), cosolvents (e.g., ethanol), buffers, and pH adjustment factors (e.g., carbonate, citrate, and phosphate solutions). The terms parenteral administration and parenterally administered, as used herein, mean modes of administration other than enteric and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and intravenous infusion. The term "pharmaceutically acceptable vehicle," as used herein, refers to a substance used in a composition to dilute any of the compounds, excipients, or components contained therein to a specified volume or weight. A pharmaceutically acceptable vehicle is either an inert substance or a substance with an action analogous to any of the elements comprising the pharmaceutical composition of the present invention. The function of such a vehicle is to allow the incorporation of other elements, to enable improved dosage and administration, or to provide consistency and form to the composition. The term prevent, the expression that prevents, and the term prevention, as used herein, refer to the inhibition of the onset or the reduction of the occurrence of a disease, condition, or symptom associated with cardiovascular calcification in a subject (e.g., the prevention of the formation or growth of PAH crystals in the coronary arteries, aorta, or aortic valve). The term SNF472, as used herein, refers to a formulation of hexasodium myo-inositol hexaphosphate. SNF472 is manufactured by dissolving hexasodium myo-inositol hexaphosphate in saline solution, followed by pH adjustment and aseptic filtration. SNF472 is prepared in three different concentrations: (a) (i) 20 mg / mL and (ii) 90 mg / mL in 5 mL single-use vials, formulated in saline solution, pH 5.8 to 6.2, and (b) 30 mg / mL in 10 mL single-use vials, formulated in saline solution, pH 5.6 to 6.4.The terms subject, individual, animal, or mammal, as used herein, mean any subject, particularly a mammalian subject, for whom a diagnosis, prognosis, or therapy is desired. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, companion animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, and cows; primates such as hominids, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; bears; edible animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters, and guinea pigs; etc. In certain respects, the subject is a human subject.In some respects, the subject is a human patient with cardiovascular calcification, or who has a disease, condition, or symptom associated with cardiovascular calcification, or is at risk of developing such cardiovascular calcification or an associated disease, condition, or symptom. In some additional respects, the subject is a human patient with coronary artery calcification, aortic artery calcification, or aortic valve calcification, or who has a disease, condition, or symptom associated with coronary artery calcification, aortic artery calcification, or aortic valve calcification, or is at risk of developing coronary artery calcification, aortic artery calcification, or aortic valve calcification, or a disease, condition, or symptom associated with any of these. The term "substantially," as used herein, refers to the qualitative condition of exhibiting the full or near-full extent or degree of a characteristic or property of interest. A person skilled in biological matters will understand that biological and chemical phenomena rarely, if ever, reach completion and / or progress to completion or achieve or avoid an absolute result. The term "substantially" is therefore used herein to capture the potential lack of completion inherent in many biological and chemical phenomena. The terms "treat" or "treatment," as used herein, refer to the administration of the compound or pharmaceutical composition of the present invention for (i) slowing, (ii) inhibiting, (iii) halting, or (iv) reversing the progression of a disease or condition after its clinical signs have appeared. Control of disease progression is understood to mean beneficial or desired clinical outcomes, including, but not limited to, symptom reduction, reduction of disease duration, stabilization of pathological states (specifically to prevent further deterioration), delay of disease progression, improvement of the pathological state, and remission (both partial and complete). Control of disease progression also implies a prolongation of survival5 compared to the expected survival without treatment.Within the context of the present invention, the terms treat and treatment specifically refer to (a) the inhibition of the formation and / or growth of additional PAH crystals in a specific area of ​​cardiovascular tissue in a subject, (b) the slowing of the evolution of the formation and / or growth of PAH crystals in a specific area of ​​cardiovascular tissue in a subject, or (c) the reduction, stopping, or elimination of the symptoms associated with cardiovascular calcification in a subject who requires it. Compounds The compounds for use in the present invention are inositol phosphates, as defined in the first aspect of the invention, as well as analogues and derivatives thereof. The term "inositol phosphate," as used herein, refers to a compound having an inositol ring and one, two, three, four, five, or six phosphate groups, or a combination thereof. Myo-inositol hexaphosphate (IP6) is an example of an inositol phosphate of the present invention. In some respects, inositol phosphate is pure (for example, more than 99% of the inositol phosphate species are of the same species, e.g., IP6) or substantially pure (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the inositol phosphate species are of the same species, e.g., IP6). In some respects, inositol phosphate is a mixture, for example, comprising varying amounts of IP1, IP2, IP3, IP4, IP5, and IP6.In some respects, inositol phosphate is a racemic mixture. The invention also contemplates inositol phosphate analogues. L 7 Rfrnn / Zznz / E / YIAI The term inositol phosphate analogue, as used herein, refers to a compound having a ring with a different number of carbons than an inositol ring (i.e., 5 or 7 carbons) and / or having at least one sulfate or thiophosphate group. For example, a compound comprising a ring with 5, 6, or 7 carbons and at least one phosphate, sulfate, or thiophosphate group would be considered an inositol phosphate analogue. The term inositol phosphate derivative, as used herein, refers to an inositol phosphate or an inositol phosphate analogue containing a heterologous moiety (i.e., a group that is not a phosphate, sulfate, or thiophosphate). For example, inositol pentasulfate comprising a heterologous polyethylene glycol moiety or myo-inositol hexaphosphate comprising a heterologous polyglycerol moiety would be considered inositol phosphate derivatives. The term heterologous moiety, as used herein, refers to a radical in the compound of Formula I that is not a phosphate, sulfate, or thiophosphate and confers a desirable property to that compound. For example, a heterologous moiety (e.g., a polyglycerol or a polyethylene glycol) may increase the solubility of the compound. In some respects, a heterologous moiety may confer multiple desirable properties (e.g., polyglycerol and polyethylene glycol may increase the solubility of a compound and reduce the clearance rate of the compound). The terms "inositol phosphate of the invention" and "inositol phosphate of the present invention," as used herein, are a generic term encompassing inositol phosphate, inositol phosphate analogue, inositol phosphate derivative, and combinations thereof. In some respects, the term "inositol phosphate of the present invention" encompasses pharmaceutical compositions comprising inositol phosphate, an inositol phosphate analogue, an inositol phosphate derivative, or a combination thereof, and pharmaceutically acceptable excipients and carriers. In some other respects, the term "inositol phosphate of the present invention" encompasses combination preparations comprising inositol phosphate, an inositol phosphate analogue, an inositol phosphate derivative, or a combination thereof, and at least one second active agent. The terms "inositol phosphate of the invention" and "inositol phosphate of the present invention," as used herein, are a generic term encompassing inositol phosphate, inositol phosphate analogue, inositol phosphate derivative, and combinations thereof. In some respects, the term "inositol phosphate of the present invention" encompasses compositions comprising an inositol phosphate, an inositol phosphate analogue, an inositol phosphate derivative, or a combination thereof, and at least one second active agent. Compounds of the present invention comprising a ring with 5, 6, or 7 carbons and at least one sulfate or thiophosphate group, but without a phosphate group, would still be considered an inositol phosphate analogue or an inositol phosphate analogue in the context of the present invention. Therefore, the term "inositol phosphate" of the present invention encompasses not only phosphate-containing compounds but also compounds without phosphate groups comprising a ring with 5, 6, or 7 carbons and at least one sulfate or thiophosphate group. Representative inositol phosphates of the present invention are shown in Figures 1-6. Figure 3 presents numerous examples of inositol phosphates, all in the myo-inositol conformation. In addition to myo-inositol, the other naturally occurring stereoisomers of inositol are escalo-, muco-, 1D-chiro-, 1L-chiro-, neo-inositol, allo-, epi-, and cis-inositol. As their names indicate, 1L- and 1D-chiro-inositol are the only pair of enantiomers of inositol, but these are enantiomers of each other, not of myo-inositol. It is understood that any example inositol phosphate presented herein is not limited to the representative conformation shown. Therefore, for example, the examples presented in Fig. 3 would also encompass the corresponding equivalents in the conformations of scilo-, muco-, ID-chiro-, IL-chiro-, neo-inositol, allo-, epi-, and cis-inositol.In its most stable conformation, the myo-inositol isomer adopts the chair configuration, which moves the maximum number of hydroxyl groups to the equatorial position, where they are spread out. In this conformation, the natural myo-inositol isomer has a structure in which five of the six hydroxyl groups (the first, third, fourth, fifth, and sixth) are equatorial, while the second hydroxyl group is axial. Inositol phosphates, analogues and derivatives In some respects, at least one of Ri, R3, Rs, R?, Rg and Ru of the compound of General Formula I independently represents H, -X, OX, -NHX, -NX2, -SX, -OSO3HX, -OSO3X2 or a compound of Formula II, Formula III or Formula IV, where each X independently represents H, C1-30 alkyl, C2-30 alkynyl or Cyi, where C1-30 alkyl, C2-30 alkenyl and C2-3C alkynyl are independently, optionally, substituted 15 with one or more R14 and where Cyi is optionally substituted by one or more R15;Cyi represents a three- to ten-membered carbocyclic or heterocyclic ring, which may be saturated, partially unsaturated, or aromatic, wherein said heterocycle has between one and four heteroatoms selected from O, S, and N, wherein said ring may be attached to the rest of the molecule through any available C atom, and wherein Cyi is optionally condensed with between one and four five- or six-membered rings, each saturated, partially unsaturated, or aromatic, carbocyclic, or heterocyclic, and wherein said condensed heterocycle may contain one or two heteroatoms selected from O, N, and S; each Ru independently represents H, C1-30 alkyl, -NH2, -NHC1-30 alkyl, or N(C1-30 alkyl)2, wherein each C1-30 alkyl is optionally independently substituted with one or more halogen groups, -OH, -CN, and -NO2;and each R14 and Ris independently represents -OH, C1-30 alkoxy, Ci-30 alkylthionyl, Ci-30 acyloxy, phosphate, halogen, C1-30 trihalo alkyl, nitrile or azide.; In some further respects, each X independently represents H, C1-30 alkyl, or Cyi, where C1-30 alkyl is optionally replaced by one or more R14 and where Cyi is optionally replaced by one or more Ri5; and each R14 and Ris independently represents -OH, C1-30 alkoxy, C1-30 alkylthionyl, C1-30 acyloxy, phosphate, halogen, C1-30 trihaloalkyl, nitrile, or azide. In some respects, each X represents H, C1-30 alkyl, or Cyi. In some respects, each X represents H. In some additional respects, at least one of the radicals Ri, R3, Rs, R?, Rg and Rn independently represents a compound of Formula II, Formula III or Formula IV, each R13 independently represents H, C1-30 alkyl, -NH2, -NHC1-30 alkyl or -N (C1-3o alkyl)2, wherein each C1-30 alkyl is independently substituted, optionally, by one or more halogen groups, -OH, -CN and -NO2; and R2, R4, Re, Rb, Rio and R12 independently represent H. In an additional aspect, Ri, R3, Rs, R?, Rg and Rn independently represent a compound of Formula II, Formula III or Formula IV, each R13 independently represents H or C1-30 alkyl, wherein each C1-30 alkyl is independently substituted, optionally, by one or more halogen, -OH, -CN and -NO2 groups; and R2, R4, Re, Rb, Rio and R12 independently represent H. In an additional aspect, at least one of Ri, Rg, R5, R7, Rg and Rn represents a compound of Formula II, Formula III or Formula IV and each R13 independently represents H or C1-30 alkyl. In another aspect, at least one of Ri, R3, R5, R7, Rg and Rn represents a compound of Formula II, Formula III or Formula IV and each R13 represents H. In one particular aspect, the compound is inositol hexaphosphate (IP6). In other aspects, the compound is inositol monophosphate (IP1), inositol diphosphate (IP2), inositol triphosphate (IP3), inositol tetraphosphate (IP4), or inositol pentaphosphate (IP5). In some aspects, the compound comprises a combination of IP1, IP2, IP3, IP4, IP5, and / or IP6. In some aspects, IP6 can form other inositol phosphates (IP5, IP4, IP3, IP2, IP1) through in vivo dephosphorylation. Inositol is understood to mean any isomeric form of the molecule, for example, myo-inositol. In some respects, the compounds for use in the present invention are those of Formula I, wherein: R7es OSOg-y Rg, Rs, R3, Ri and Rn are selected independently of OPO32-, OPSO22' or 0S03; Rg, R5y Rison OPO32y R7, R3 and Rn are OSOg”; Rg, R5 and Ri are OSO3· and R7, R3 and Rn are OPO32·; R3, Rg and Rn are OSOg- and Rg, R7 and Rs are OPOs2-; R3, Ri and Rn are OPOs2-and Rg, R7 and Rs are OSO3V R7y Rison OPO32-and Rg, Rs, R3 and Rn are OPOg2-; R7 and Ri are OSO3 and Rg, Rs, R3 and Rn are OPOg2-; R7y R are OPO32y Rg, R3, Ri and Rn are OSO3; either, R7 and Rs are OSO3 and Rg, R3, Rs and Rn are OPO32. The inositol phosphates of the present invention also encompass compounds that are produced as metabolites during physiological dephosphorylation (or desulfation or destrosulfation, in the case of compounds comprising sulfate or thiophosphate groups). In some respects, the compound administered in a dosage according to the methods disclosed herein is a prodrug that, after undergoing hydrolysis or other intracellular or extracellular processing, yields an inositol phosphate of the present invention. The inositol phosphates of the present invention also encompass any combination of inositol phosphate, inositol phosphate analogues, and derivatives thereof disclosed herein. All Formula I compounds contain radicals with COP or COS linkages, which give the compounds an affinity for calcium-containing crystals and a bond labile enough to be hydrolyzed in vivo. This prevents irreversible binding to calcium-containing crystals, such as hydroxyapatite (HAP), in bone, which would negatively impact bone remodeling. This is the case with bisphosphonates when administered long-term, as these compounds contain PCP linkages that cannot be hydrolyzed by the body. At the other extreme are phosphorylated compounds that do not contain such COP linkages, such as pyrophosphates, whose POP linkages mean they are too easily hydrolyzed in the intestine, thus making parenteral administration the only feasible option.The compounds of the present invention, with COP bonds and C-OS bonds, and combinations thereof, represent a suitable intermediate point due to their effectiveness and the fact that the body has mechanisms for the elimination of said compounds, thus reducing the risk of side effects (for example, compounds with PCP bonds may have half-lives of several months which, in vivo, affect, for example, bone remodeling). The term alkyl or the expression alkyl group in the context of the present invention refers to a saturated hydrocarbon residue, which may be linear, branched, cyclic, or cyclic with linear or branched side chains. The term alkyl includes partially unsaturated hydrocarbons, such as propenyl. Examples include methyl, ethyl, n- or isobutyl, and n- or cyclohexyl. The term alkyl may be extended to alkyl groups connected or bridged by heteroatoms. The heteroatoms in the context of the present invention are nitrogen (N), sulfur (S), and oxygen (O). An amine function or amine group is an NR'R'' function, with R' and R'' selected independently from hydrogen and C5C5 alkyl. In some respects, R' and R'' are selected from hydrogen and C1-C3 alkyl. A hydroxy function or hydroxy group is OH. A thiol functional group is SH. A carboxylic acid functional group is COOH or its anion, COOH. A carboxylic amide is CONR'R'', where R' and R'' have the meanings indicated above. A sulfonic acid is SO3H. A sulfonic acid amide is SO2NR'R'', where R' and R'' have the meanings indicated above. A C1-C3 alkyl in the context of the present invention refers to a linear or branched saturated hydrocarbon having 1, 2, or 3 carbon atoms, wherein a carbon-carbon bond may be unsaturated and a CH2 group may be replaced by oxygen (ether bridge). Non-limiting examples of a C1-C3 alkyl are methyl, ethyl, propyl, prop-2-enyl, and prop-2-ynyl. A C1-C5 alkyl in the context of the present invention refers to a linear or branched saturated hydrocarbon having 1, 2, 3, 4, or 5 carbon atoms, wherein one or two carbon-carbon bonds may be unsaturated and a CH2 group may be replaced by oxygen (ether bridge). Non-limiting examples of a C1-C5 alkyl include the C1-C3 alkyl examples given above and, additionally, n-butyl, 2-methylpropyl, tert-butyl, 3-methylbut-2-enyl, 2-methylbut-3-enyl, 3-methylbut-3-enyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,2-dimethylpropyl, but-3-enyl, but-3-ynyl, and pent-4-ynyl. A C3-C10 alkyl in the context of the present invention refers to a linear or branched saturated hydrocarbon having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, wherein 1, 2 or 3 carbon-carbon bonds may be unsaturated and a CH2 residue may be exchanged for oxygen (ether bridge). The expression C1-30 alkyl, as a group or part of a group, refers to a linear or branched chain alkyl group containing between 1 and 30 carbon atoms, including, among others, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tere-butyl, pentyl, hexyl, decyl and dodecyl groups. The term C2-30 alkenyl refers to a linear or branched alkyl chain containing between 2 and 30 carbon atoms and one or more double bonds. Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, isopropenyl-1-butenyl, 2-butenyl, 3-butenyl, and 1,3-butadienyl. The term C2-30 alkynyl refers to a linear or branched alkyl chain containing between 2 and 30 carbon atoms and also containing one or more triple bonds. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1,3-butadiynyl. A Cyi group refers to a three- to ten-membered carbocyclic or heterocyclic ring that may be saturated, partially unsaturated, or aromatic and is attached to the rest of the molecule through any available carbon atom. When heterocyclic, Cyi contains one to four heteroatoms selected from nitrogen, oxygen, and sulfur. Additionally, Cyi can optionally condense with up to four five- or six-membered carbocyclic or heterocyclic rings, which may be saturated, partially unsaturated, or aromatic. If the condensed ring is a heterocycle, it contains one or two heteroatoms selected from nitrogen, oxygen, and sulfur.Examples of Cyi include, but are not limited to, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzothiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl and aziridinyl. A C1-30 alkoxy group, either as a group or as part of a group, refers to a C1-30 -Oalkyl group, where the C1-30 alkyl part has the same meaning as above. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. A C1-30 alkylthionyl group, either as a group or as part of a group, refers to a C1-30 -SOalkyl group, where the C1-30 alkyl part has the same meaning as above. Examples include methylthionyl, ethylthionyl, propylthionyl, isopropylthionyl, butylthionyl, isobutylthionyl, sec-butylthionyl, and tert-butylthionyl. A C1-30 acyloxy group, as a group or part of a group, refers to a C1-30 -COalkyl group, where the C1-30 alkyl part has the same meaning as above. Examples include acetyl, ethanoyl, propanoyl, and 2,2-diisopropylpentanoyl. A halogen radical, or the abbreviation halo, refers to fluorine, chlorine, bromine, and iodine. A C1-30 trihalo alkyl group refers to a group resulting from the substitution of three hydrogen atoms of a C1-30 alkyl group by three halogen radicals, as defined above. Examples include, but are not limited to, trifluoromethyl, tribromomethyl, trichloromethyl, triiodomethyl, trifluoroethyl, tribromoethyl, trichloroethyl, triiodoethyl, tribromopropyl, trichloropropyl, and triiodopropyl. A C1-30 -NHalkyl group refers to a group resulting from the substitution of a hydrogen atom of an -NH2 group by a C1-30 alkyl group, as defined above. Examples include, but are not limited to, methylamine, ethylamine, propylamine, butylamine, and pentylamine. An -N(C1-30)2 group refers to a group resulting from the substitution of two hydrogen atoms of an -NH2 group by a C1-30 alkyl group, as defined above. Examples include, but are not limited to, dimethylamine, diethylamine, diisopropylamine, dibutylamine, and diisobutylamine. The expression "optionally substituted by one or more" means that a group can be substituted by one or more (for example, 1, 2, 3, or 4) substituents. In some respects, a group can be substituted by 1, 2, or 3 substituents, or even by 1 or 2 substituents, provided the group has enough available substitutable positions. If present, the substituents can be the same or different and can be located in any available position. In some respects, the inositol phosphates of the present invention comprise the compounds disclosed in documents WO2017098033 and WO2017098047 and US9358243. In some respects, the inositol phosphates of the present invention used comprise the compounds disclosed in Fig. 1-6. In some respects, inositol phosphates, inositol phosphate analogues, and derivatives thereof comprise compounds of Formula (VIII), Formula (IX), or Formula (X): wherein each X is independently selected from OPOa2-, OPSO22- or OSO3~; Z is an alkyl chain comprising 1 to 3 carbon atoms and / or heteroatoms, optionally comprising an X group, wherein X is also selected from OPO32, OPSO22- or OSO3; and R1 is an optional heterologous moiety (see section 2.2 below). In some respects, the molecule comprises more than one heterologous moiety, in which case the heterologous moiety may be the same or different. In some respects, Z, as used in Formula (VIII), is CH2, CHX, CHR1, CXR1, CH2-CH2, CH2-CHX, CHX-CHX, CHR'-CHX, CXP^CEX, CHR1CH2, CXR1-CH2, CHRí-CHOH, CH2-CH2-CH2, CH2-O-CH2, CHOH-CH2-CH2, CHOH-CHOHCHR1, CHOH-CHR1-CHOH, CHX-CH2-CH2, CH2-CHX-CH2, CHX-CHX-CH2, CHX-CH2-CHX or CHX-CHR1-CHX, wherein X is selected independently from OPO32, OPSO22^ and OSO3-. In some respects, Z, as used in Formula (VIII), is (CHX)PCHX(CHX)q; wherein p and q each independently have a value from 0 to 2, provided that (p+q) has a value of 0, 1, or 2; one, two, or three X's may be a heterologous residue (e.g., PEG), and the remaining X's are selected independently of OPO32, OPSO22·, and OSO3. In some respects, not all X's in Z are OPOs2-. In some respects, not all X's in Z are OSOs-. In some respects, one, two, or three of the X's in the compounds of Formula (VIII), Formula (IX), or Formula (X) may be a heterologous residue, and the remaining X may be selected independently of OPO32U, OPSO22, or OSCV. Formula (VII) above describes a five-membered, six-membered, or seven-membered alkyl ring and the optional heterologous residue(s) are attached to one of the carbon atoms forming the ring. In some respects, inositol phosphates, inositol phosphate analogues, and derivatives thereof used, for example, in the methods and compositions disclosed herein, comprise compounds of Formula (XI) or Formula (XII): L 7 Rfrnn / Zznz / E / YIAI (XI) (XII) where: X2 is OSO3” and X1, X3, X4, X5 and X6 are selected independently of OPO32-, OPSO22- or OSO3; X1, X3 and X5 are OPO32· and x2. X4 and X6 are OSO3-; X1, X3 and X5 are OSO3- and x2, X4 and X6 are OPO30 X4, X5and X6are OPO32and X1, X2and X2 and X5 are OPO32-and X1, X3, X4 and X6 are ΟΡΟ32; X2 and X5 are OSO3- and X1, X3, X4 and X6 are OPO32-; X2 and X3 are OPO32~ and X1, X4, X5 and X6 are OSO3~; either, X2 and X3 are OSO3~ and X1, X4, X5 and X6 are OPO32v In some respects, the inositol phosphates of the present invention or their metabolites can be detected and / or quantified using the methods disclosed in US9612250. See also US8377909, US8778912 and US20070066574. The compounds disclosed herein may be present in any form commonly used in pharmaceutical technology. Particular aspects include, but are not limited to, the sodium salt, magnesium salt, potassium salt, ammonium salt, free acid, or a mixture of the foregoing forms. Other pharmaceutically acceptable salts are known to those skilled in the art and readily available. In one particular aspect, the compound for use as defined in the first aspect of the invention is a sodium salt, for example, hexasodium inositol hexaphosphate. The present invention also includes sodium salts of inositol monophosphate, inositol diphosphate, inositol triphosphate, inositol tetraphosphate, and inositol pentaphosphate in any of the isomeric forms of inositol, in particular, myo-inositol. A particular example of the compounds for use in the present invention is the hexasodium salt of myo-inositol hexaphosphate. Heterologous remainder In some respects, the present invention relates to a compound of general Formula I, as defined above, wherein the heterologous residue is selected from a radical of Formula V, a radical of Formula VI, and a radical of Formula VII: L 7 Rfrnn / Zznz / E / YIAI VII and where n is an integer in the interval from 2 to 200 and R13 is selected from H, methyl or ethyl. In some respects, the compounds for use in the present invention, for example, the inositol phosphate derivatives of the present invention, may comprise one or two radicals selected from the radicals of Formulas V, VI, and VII. These radicals are heterologous moieties that confer an advantageous property with respect to a corresponding molecule lacking such a moiety or moieties.Examples of such advantageous properties that can be conferred by a heterologous moiety or a combination thereof to inositol phosphate or inositol phosphate analogues include, but are not limited to, (a) increased solubility, (b) decreased rate of degradation or metabolism, (c) increased plasma half-life, (d) decreased rate of hepatic metabolism, (e) decreased clearance rate, (f) decreased toxicity, (g) decreased irritability, and (h) reduced side effects. These advantageous properties can be evaluated or quantified using methods known in the art without excessive experimentation. In some aspects, the heterologous moiety is, for example, a polyethylene glycol (PEG) or a polyglycerol (PG). Therefore, in certain aspects, the compound for use in the invention is any of the compounds defined in the aspects disclosed above comprising a heterologous moiety, i.e., one of the radicals of Formula I is selected from the radicals of Formulas V, VI, and VII. In some aspects, the heterologous moiety comprises a polyethylene glycol (PEG). In certain aspects, the heterologous moiety consists of polyethylene glycol, i.e., at least one of Ri, R3, R5, R6, Rg, and R11 of the compound of Formula I, according to the first aspect of the invention, is a radical of Formula V. Alternatively, the heterologous moiety comprises a polyglycerol.In certain aspects, the heterologous residue consists of polyglycerol, i.e., at least one of Ri, R3, Rs, Rβ, Rg, and Rn of the compound of Formula I, according to the first aspect of the invention, is selected from a radical of Formula VI or VII. In other aspects, the compound of Formula I, according to the first aspect of the invention, contains one, two, or three radicals selected from a radical of Formula VI or VII, for example, two PEGs (radical of Formula V), three PEGs, two polyglycerols (radical of Formula VI), three PGs, or any combination thereof, for example, one PEG and one PG, or two PEGs and one polyglycerol. In certain aspects, all the remaining radicals of Formula I (i.e., those that are not a radical selected from V, VI, and VII) are a radical selected from II, III, and IV.In some aspects, the compound of Formula I, according to the first aspect of the invention, contains two radicals selected from a radical of Formula VI or VII, for example, two PEGs (radical of Formula V) or two polyglycerols (radical of Formula VI) or one PEG and one polyglycerol, and the remaining radicals are all a radical of Formula II. In some aspects, R3 and R? of the compound of Formula I are selected from a radical of Formula V, VI, and VII. In some aspects, R3 and R? of the compound of Formula I are radicals of Formula V, and Ri, R5, Rg, and Rn of the compound of Formula I are radicals of Formula II. The radicals of Formulas V, VI, and VII have R13 = H, methyl, or ethyl, and n is an integer from 2 to 200. In some respects, R13 = H. In particular, n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30. 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 , 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 , 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 , 97, 98, 5 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 10 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 189, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199 o 200. L 7 Rfrnn / Zznz / E / YIAI In some respects, n is between 2 and 10, between 10 and 20, between 20 and 30, between 30 and 40, between 40 and 50, between 50 and 60, between 60 and 70, between 70 and 80, between 80 and 90, between 90 and 100, between 100 and 110, between 110 and 120, between 120 and 130, between 130 and 140, between 140 and 150, between 150 and 160, between 160 and 170, between 170 and 180, between 180 and 190 or between 190 and 200. In some specific aspects, n has a value of 2 to 200, 20 to 20, 10 to 30 or 9 to 45. In some respects, PEG is a branched PEG. Branched PEGs have three to ten PEG chains branching off from a central core group. In certain respects, the PEG residue is a monodisperse polyethylene glycol 25. In the context of the present invention, a monodisperse polyethylene glycol (mdPEG) is a PEG having a unique and defined chain length and molecular weight. mdPEGs are typically generated by separating the polymerization mixture using chromatography. In certain formulations, a monodisperse PEG residue is designated as mdPEG. In some respects, the PEG is a star-type PEG. Star-type PEGs have 10 to 100 PEG chains branching off from a central core group. In some respects, PEG is a comb-type PEG. Comb-type PEGs have multiple PEG chains typically grafted onto a main polymer chain. In certain aspects, PEG has a molar mass between 100 g / mol and 3,000 g / mol, particularly between 100 g / mol and 2,500 g / mol, more specifically from approximately 100 g / mol to 2,000 g / mol. In certain aspects, PEG has a molar mass between 200 g / mol and 3,000 g / mol, particularly between 300 g / mol and 2,500 g / mol, more specifically from approximately 400 g / mol to 2,000 g / mol. In some aspects, PEG is PEGioo, PEG200, PEG300, PEG400, PEG500, PEGgoo, PEG700, PEGgoo, PEG900, PEG1000, PEGuoo, PEG1200, PEG1300, PEG1400, PEG1500, PEGieoo, PEG1700, PEGisoo, PEG1900, PEG2000, PEG2100, PEG2200, PEG230C, PEG2400, PEG2500, PEGieoo, PEG1700, PEGisoo, PEG1900, PEG2000, PEG2100, PEG2200, PEG2300, PEG2400, PEG2500, PEG2600, PEG2700, PEG2800, PEG2900 or PEG3000. In one particular aspect, PEG is PEG400. In another particular aspect, PEG is PEG2000 · In some respects, the inositol phosphate of the invention is an mdPEG inositol phosphate derivative modified at positions 4 and 6. In some respects, the inositol phosphate of the invention is inositol-1,2,3,5-tetraphosphate-4,6-bisPEG2oo, inositol-1,2,3,5-tetraphosphate-4,6-bisPEG3oo, inositol-1,2,3,5-tetraphosphate-4,6-bisPEG4oo, inositol-1,2,3,5-tetraphosphate-4,6-bisPEGsoo, inositol-1,2,3,5-tetraphosphate-4,6-bisPEGsoo, inositol-1,2,3,5-tetraphosphate-4,6-bisPEG7oo, inositol-1,2,3,5-tetraphosphate-4,6-bisPEGsoo, inositol-1,2,3, 5-tetraphosphate-4,6-bisPEGgoo or inositol-1,2,3,5-tetraphosphate-4,6-bisPEGiooo In some respects, the inositol phosphate of the invention is inositol-1,2,3,5-tetraphosphate-4,6-bisPEGioo. In other particular aspects, R3 and / or R7 of the compound of Formula I is a radical of Formula V, where R13 is H and n is an integer from 9 to 45. In other particular aspects, R3 and R7 of the compound of Formula I is a radical of Formula V, where R13 is H and n is an integer from 9 to 45 and Ri, R5, Rg, and Ru are all radicals of Formula II. In other particular aspects, the compound of Formula I is a sodium salt with R3 and R7 = radical of Formula V, where R13 is H and n is an integer from 9 to 45 and Ri, R5, Rg, and Ru are all radicals of Formula II. In some other aspects, the heterologous moiety is a polyglycerol (PG) described by the formula ((R3-O-(CH2-CHOH-CH2O)n-), where R3 is hydrogen, methyl, or ethyl and n has a value from 3 to 200. In some aspects, n has a value from 3 to 20. In some aspects, n has a value from 10 to 30. In some alternatives of these aspects, n has a value from 9 to 45. In some aspects, the heterologous moiety is a branched polyglycerol described by the formula (R3-O-(CH2-CHOR5CH2-O)n-), where R5 is hydrogen, or a linear glycerol chain described by the formula (R3-O-(CH2-CHOH-CH2-O)n~) and where R3 is hydrogen, methyl, or ethyl.In some respects, the heterologous remainder is a hyperbranched polyglycerol described by the formula (R3-O-(CH2CHOR5-CH2-O)n-), where R5 is hydrogen or a glycerol chain described by the formula (R3-O-(CH2-CHOR6-CH2-O)n-), where R6 is hydrogen or a glycerol chain described by the formula (R3-O-(CH2-CHOR7CH2-O)n-), where R7 is hydrogen or a linear glycerol chain described by the formula (R3-O-(CH2-CHOH-CH2-O)n-), where R3 is hydrogen, methyl, or ethyl. Hyperbranched glycerol and methods for its synthesis are known in the art (Oudshorn M, et al., Biomaterials 2006; 27:5471-5479, Wilms D, et al., Acc Chem Res 2010; 43:129-141) and the references cited therein. In certain aspects, PG has a molar mass between 100 g / mol and 3,000 g / mol, particularly between 100 g / mol and 2,500 g / mol, more specifically from approximately 100 g / mol to 2,000 g / mol. In certain aspects, PG has a molar mass between 200 g / mol and 3,000 g / mol, particularly between 300 g / mol and 2,500 g / mol, more specifically from approximately 400 g / mol to 2,000 g / mol. In some aspects, the PG is PG100, PG200, PG300, PG400, PG500, PGgoo, PG700, PGsoo, PG900, PG1000, PGnoo, PG1200, PG1300, PG1400, PG1500, PGieoo, PG1700, PG1800, PGi900, PG2000, PG2100, PG2200, PG2300, PG2400, PG2500, PG1600, PG1700, PG1800, PG1900, PG2000, PG2100, PG2200, PG2300, PG2403, PG2500, PG2600, PG2700, PG2800, PG2900, or PG3000. In one particular aspect, the PG is PG400. In another particular aspect, the PG is PG2000. In other specific aspects, R3 and / or R7 of the Formula compound I is a radical of Formula VI, where R13 is H and n is an integer from 9 to 45. In other particular aspects, R3 and R? of the compound of Formula I are a radical of Formula VI, where R13 is H and n is an integer from 9 to 45 and Ri, R5, Rg and Ru are all a radical of Formula II. In other particular aspects, the compound of Formula I is a sodium salt with R3 and R7= radical of Formula VI, where R13 is H and n is an integer from 9 to 45 and Ri, R5, Rg and Ru are all a radical of Formula II. Pharmaceutical compositions and combination preparations In another aspect, the present invention also relates to pharmaceutical compositions comprising a compound, as defined in any of the aspects disclosed above. In some aspects, the pharmaceutical composition comprises a compound, as defined in any of the aspects disclosed above, together with one or more pharmaceutically acceptable excipients or carriers. In some aspects, these pharmaceutical compositions are for use in the treatment, inhibition of progression, or prevention of (a) cardiovascular calcification, or (b) a disease, condition, or symptom associated with cardiovascular calcification in a subject who requires it or (c) is at risk of developing such cardiovascular calcification, disease, condition, or associated symptom.In some additional aspects, the pharmaceutical compositions of the invention are for use in the treatment, inhibition of progression, or prevention of (a) coronary artery calcification, aortic artery calcification, or aortic valve calcification in subjects who require it, or (b) a disease, condition, or symptom associated with coronary artery calcification, aortic artery calcification, or aortic valve calcification, or (c) individuals at risk of developing coronary artery calcification, aortic artery calcification, or aortic valve calcification, or a disease, condition, or symptom associated with any of the same. In some additional aspects, the pharmaceutical compositions of the invention comprise a combination preparation comprising at least one second active agent. The pharmaceutical compositions may comprise from approximately 95% of the compound, as defined in any of the aspects disclosed above. In some aspects, the pharmaceutical compositions of the present invention may comprise, for example, from approximately 20% to approximately 90%, or from 20% to 80%, or from 20% to 70%, or from 20% to 60%, or from 20% to 50%, or from 30% to 90%, or from 40% to 90%, or from 50% to 90%, or from 60% to 90%, or from 30% to 70% of the compound, as defined in any of the aspects disclosed above. In some aspects, the concentration of inositol phosphate of the present invention (e.g., myo-inositol hexaphosphate or an analogue or derivative thereof or a combination thereof) in each dose of the pharmaceutical composition is between approximately 12.5 mM and approximately 135 mM. In some versions of this aspect, the concentration of inositol phosphate of the present invention (e.g., myo-inositol hexaphosphate or an analogue or derivative thereof or a combination thereof) in each dose of the pharmaceutical composition is approximately 25 mM, approximately 39 mM, or approximately 114 mM. Pharmaceutical formulations suitable for parenteral administration comprise a compound, as defined in any of the aspects disclosed above, mixed with a pharmaceutically acceptable carrier (e.g., sterile water or sterile isotonic saline). Such formulations may be prepared, packaged, or marketed in a form suitable for bolus or continuous administration. Injectable formulations may be prepared, packaged, or marketed in unit dosage forms, such as ampoules or multi-dose containers containing a preservative. Parenteral formulations include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable, sustained-release, or biodegradable formulations.Such formulations may also include one or more additional ingredients, including, but not limited to, suspending agents, stabilizers, or dispersants. In some aspects, in a formulation for parenteral administration, the active agent (e.g., a compound, as defined in any of the aspects disclosed above) is provided in dry form (i.e., powder or granules) for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition. Pharmaceutical compositions may be prepared, packaged, or marketed as a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to known art and may comprise, in addition to the active agent (e.g., the compound, as defined in any of the aspects disclosed above), additional ingredients, such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a nontoxic, parenterally acceptable diluent or solvent, such as water or 1,3-butanediol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils, such as synthetic monoglycerides or diglycerides. Other parenterally administerable formulations that are useful include those comprising the active agent (e.g., the compound, as defined in any of the aspects disclosed above) in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials, such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt. Controlled-release or sustained-release formulations of a pharmaceutical composition of the present invention can be prepared using conventional technology. In some cases, the dosage forms to be used can be provided as slow-release or controlled-release formulations of one or more of the active agents therein using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres, or a combination thereof, to provide the desired release profile in varying proportions. Suitable controlled-release formulations known in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention.Therefore, individual unit pharmaceutical forms suitable for parenteral or topical administration, such as injectable solutions, gels, creams, and ointments, adapted for controlled release, are covered in the present invention. Most controlled-release products share the common goal of improving therapy compared to their non-controlled counterparts. Ideally, the optimal use of a controlled-release preparation in medical treatment is characterized by the use of a minimal amount of active agent to cure or control the condition in a minimal amount of time. The advantages of controlled-release formulations include prolonged activity of the active agent, reduced dosing frequency, and increased patient compliance. Furthermore, controlled-release formulations can be used to influence the onset of action or other characteristics, such as the blood level of the active agent, and thus can influence the occurrence of side effects. Most controlled-release formulations are designed to initially release an amount of active agent that immediately produces the desired therapeutic effect and then gradually and continuously release additional amounts of active agent to maintain this level of therapeutic effect over a prolonged period. To maintain this constant level of active agent in the body, the active agent must be released from the dosage form at a rate that replaces the amount of active agent that is metabolized and excreted from the body. The controlled release of an active agent can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled-release component" in the context of the present invention is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres, or a combination thereof, that facilitate the controlled release of the active agent. In certain aspects, the formulations of the present invention may be, but are not limited to, short-term release formulations, rapid compensation formulations, as well as controlled release formulations, for example, sustained release, delayed release, and pulsatile release. The term sustained release is used in its conventional sense to refer to an active agent formulation (e.g., the compound, as defined in any of the aspects disclosed above) that provides the gradual release of a therapeutic active agent over a prolonged period and that may, but does not necessarily, result in substantially constant blood levels of the active agent over a prolonged period. The time period may be up to a month or more and should be a release that is greater than that of the same amount of agent administered as a bolus. In sustained-release formulations, the compounds can be formulated with a suitable polymer or hydrophobic material that provides sustained-release properties. As such, the compounds for use in the method of the present invention can be administered in the form of microparticles, for example, by injection, or in the form of wafers or discs by implantation. In certain aspects, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained-release formulation. The term delayed release is used herein in its conventional sense to refer to an active agent formulation that provides initial release of the active agent after a delay following administration. The delay may range from approximately 10 minutes to approximately 12 hours. The term pulsatile release is used herein in its conventional sense to refer to an active agent formulation that provides release of the active agent in such a manner as to produce pulsed plasma profiles of the active agent following administration. The term immediate release is used herein in its conventional sense to refer to an active agent formulation that provides release of the active agent immediately following administration. In the context of the present invention, the expression "non-bolus prolonged-release form" refers to the administration of an active agent to a subject that lasts for at least 1 minute, in the case of a parenteral injection, for example, an intravenous injection or a subcutaneous injection, and for at least 30 minutes, in the case of a parenteral infusion, for example, an intravenous infusion. Additional formulations and pharmaceutical forms of the compositions of the present invention include pharmaceutical forms, as described in documents US6340475, US6488962, US6451808, US5972389, US5582837 and US5007790; documents US20030147952, 20030104062, 20030104053, 20030044466, 20030039688 and 20020051820; documents WO 2003035041, WO2003035040, WO2003035029, WO200335177, WO2003035039, WO2002096404, WO2002032416, WO2001097783, WO2001056544, WO2001032217, WO1998055107, WO1998011879, WO1997047285, WO1993018755 and WO1990011757. The medicinal products according to the invention are manufactured by methods known in the art, especially by mixing, coating, granulation, dissolution or conventional lyophilization. The present invention also provides a compound, a combination of compounds, or a pharmaceutical formulation, as defined in any of the foregoing aspects of the invention, in the broader definition given, or as specified in any of the aspects presented above, for use as a medicament. An additional aspect of the present invention relates to a combination preparation comprising (a) a compound and / or (b) a pharmaceutical composition according to the present invention and (c) at least one second active agent. These second active agents are regularly administered to subjects with renal insufficiency. In some aspects, the combination preparation is administered to subjects undergoing dialysis. Some of these second active agents alter the thermodynamics of the PAH crystallization process by modifying the concentration of ions present in the calcium-containing crystal structure that is directly or indirectly responsible for the renal insufficiency-related disease. Therefore, in some respects, the second active agent is selected from the group consisting of a vitamin, a calcimimetic, a bisphosphonate, a phosphate binder, a thiosulfate, a pyrophosphate, a citrate, a diuretic, an antihypertensive, an anticholesterolemic agent, a phosphodiesterase inhibitor, and combinations thereof. In some respects, the vitamin in the combined preparation is vitamin B, vitamin D, vitamin K, or a combination thereof. In some respects, the calcimimetic in the combination preparation is cinacalcet ((R)-N-[l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-l-amine, KAI-4169 (etelcalcetide), NPS R467 (((R)-N-(3-phenylpropyl)-1-(3-methoxyphenyl)ethylamine)), NPS R-568 ((R)-2-chloro-N-(1-(3-methoxyphenyl)ethyl)benzenepropanamine), or a combination thereof. In some respects, the bisphosphonate in the combination preparation may contain nitrogen or be nitrogen-free. In some additional respects, the bisphosphonate is alendronate, clodronate, etidronate, ibandronate, monidronate, neridronate, olpadronate, pamidronate, parnidronate, risedronate, tiludronate, zoledronate, or a combination of the same. In some aspects, the phosphate binder in the combination preparation is an aluminum salt, a calcium salt, an iron salt, a lanthanum salt, a magnesium salt, a sevelamer salt, or a combination thereof. In some additional aspects, the phosphodiesterase inhibitor in the combination preparation is cilostazol, pentoxifylline, or a combination thereof. In some respects, the diuretic in the combination preparation is a thiazide, a thiazide-like product (e.g., indapamide, chlorthalidone, metolazone), a loop diuretic (e.g., bumetanide, ethacrynic acid, furosemide, torsemide), a carbonic anhydrase inhibitor, an osmotic diuretic, or a potassium-sparing diuretic. In some additional respects, the thiazide is chlorothiazide, epithiazide, bendroflumethiazide, hydrochlorothiazide, or a combination thereof. In some respects, the antihypertensive in the combination preparation is a diuretic, an adrenergic blocker (e.g., beta-blocker, alpha-blocker, or a combination thereof), a calcium channel blocker (e.g., dihydropyridine), a renin inhibitor, an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, an aldosterone antagonist, a vasodilator, an alpha-2 agonist, or a blood pressure vaccine. In some additional respects, the cholesterol-lowering agent in the combination preparation is a statin, a fibrate, niacin, a bile acid sequestrant, ezetimibe, lomitapide, a phytosterol, orlistat, or a combination thereof. In some aspects, (a) a compound and / or (b) a pharmaceutical composition according to the present invention and (c) at least one second active agent of the combined preparation are administered separately, simultaneously, or sequentially to a subject in need. In some additional aspects, (a) a compound and / or (b) a pharmaceutical composition according to the present invention and (c) at least one second active agent of the combined preparation are mixed prior to administration to the subject in need. Methods and routes of administration In some respects, the administration of an effective amount of a compound, pharmaceutical composition, or combination preparation, as defined in any of the preceding aspects, is provided. Such compound, pharmaceutical composition, or combination preparation may be administered parenterally, such as intravenously, intraperitoneally, intramuscularly, intra-arterially, intradermally, intrathecally, epidurally, spinally, or subcutaneously. Parenteral administration may be by bolus injection or intravenous infusion. In one particular aspect of the present invention, myo-inositol hexaphosphate (or a formulation comprising myo-inositol hexaphosphate, such as SNF472) is administered by intravenous infusion. In another particular aspect of the present invention, myo-inositol hexaphosphate is administered subcutaneously. In another aspect, an inositol derivative or myo-inositol hexaphosphate derivative, for example, a compound of Formula I with R3 and R7 being radicals of Formula V, where R13 is H and n is an integer from 2 to 200, and Ri, Rs, Rg, and Rn are all radicals of Formula II (or a sodium salt thereof), is administered by intravenous infusion. In another aspect, an inositol derivative or myo-inositol hexaphosphate derivative, for example, a compound of Formula I with R3 and R7 = radical of Formula V, where R13 is H and n is an integer from 2 to 200 and Ri, Rs, Rg and Rn are all a radical of Formula II (or a sodium salt thereof), is administered subcutaneously. In some aspects, the inositol phosphate dose of the present invention comprises approximately 200 mg to approximately 700 mg of an inositol phosphate, an inositol phosphate analogue, an inositol phosphate derivative, or a combination thereof per administration. In some aspects, when the disease or condition treated or prevented is related to coronary artery calcification, aortic artery calcification, or aortic valve calcification in a subject with renal impairment (e.g., patients with stage 5 CKD), the dose is approximately 300 mg to 600 mg of the inositol phosphate of the invention per administration. In some respects, the inositol phosphate dosage of the present invention (for example, myo-inositol hexaphosphate) is between approximately 200 mg and approximately 300 mg, between approximately 300 mg and approximately 400 mg, between approximately 400 mg and approximately 500 mg, between approximately 500 mg and approximately 600 mg, or between approximately 600 mg and approximately 700 mg per administration. In some respects, the inositol phosphate dosage of the present invention (e.g., myo-inositol hexaphosphate) is between approximately 200 mg and approximately 250 mg, between approximately 250 mg and approximately 300 mg, between approximately 300 mg and approximately 350 mg, between approximately 350 mg and approximately 400 mg, between approximately 400 mg and approximately 450 mg, between approximately 450 mg and approximately 500 mg, between approximately 500 mg and approximately 550 mg, between approximately 550 mg and approximately 600 mg, or between approximately 650 mg and approximately 700 mg per administration. In some respects, the inositol phosphate dosage of the present invention (for example, myo-inositol hexaphosphate) is between approximately 200 mg and approximately 400 mg, between approximately 300 mg and approximately 500 mg, between approximately 400 mg and approximately 600 mg, between approximately 500 mg and approximately 700 mg, between approximately 200 mg and approximately 500 mg, between approximately 300 mg and approximately 600 mg, or between 400 mg and approximately 700 mg per administration. In some respects, the inositol phosphate dosage of the present invention (e.g., myo-inositol hexaphosphate) is approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg,Approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, or approximately 700 mg per administration. In some respects, the inositol phosphate dosage of the present invention (e.g., myo-inositol hexaphosphate) is between approximately 210 mg and approximately 700 mg, between approximately 220 mg and approximately 700 mg, between approximately 230 mg and approximately 700 mg, between approximately 240 mg and approximately 700 mg, between approximately 250 mg and approximately 700 mg, between approximately 260 mg and approximately 700 mg, between approximately 270 mg and approximately 700 mg, between approximately 280 mg and approximately 700 mg, between approximately 290 mg and approximately 700 mg, between approximately 300 mg and approximately 700 mg, between approximately 310 mg and approximately 700 mg, between approximately 320 mg and approximately 700 mg, between approximately 330 mg and approximately 700 mg, between approximately 340 mg and approximately 700 mg, between approximately 350 mg and approximately 700 mg,between approximately 360 mg and approximately 700 mg, between approximately 370 mg and approximately 700 mg, between approximately 380 mg and approximately 700 mg, between approximately 390 mg and approximately 700 mg, between approximately 400 mg and approximately 700 mg, between approximately 410 mg and approximately 700 mg, between approximately 420 mg and approximately 700 mg, between approximately 430 mg and approximately 700 mg, between approximately 440 mg and approximately 700 mg, between approximately 450 mg and approximately 700 mg, between approximately 460 mg and approximately 700 mg, between approximately 470 mg and approximately 700 mg, between approximately 480 mg and approximately 700 mg, between approximately 490 mg and approximately 700 mg, between approximately 500 mg and approximately 700 mg, between approximately 510 mg and approximately 700 mg, between approximately 520 mg and approximately 700 mg, between approximately 530 mg and approximately 700 mg,between approximately 540 mg and approximately 700 mg, between approximately 550 mg and approximately 700 mg, between approximately 560 mg and approximately 700 mg, between approximately 570 mg and approximately 700 mg, between approximately 580 mg and approximately 700 mg, between approximately 590 mg and approximately 700 mg, between approximately 600 mg and approximately 700 mg, between approximately 610 mg and approximately 700 mg, between approximately 620 mg and approximately 700 mg, between approximately 630 mg and approximately 700 mg, between approximately 640 mg and approximately 700 mg, between approximately 650 mg and approximately 700 mg, between approximately 660 mg and approximately 700 mg, between approximately 670 mg and approximately 700 mg, between approximately 680 mg and approximately 700 mg, or between approximately 690 mg and approximately 700 mg per administration. In some respects, the inositol phosphate dosage of the present invention (for example, myo-inositol hexaphosphate) is between approximately 200 mg and approximately 210 mg. L 7 Rfrnn / Zznz / E / YIAI approximately 200 mg and approximately 220 mg, between approximately 200 mg and approximately 230 mg, between approximately 200 mg and approximately 240 mg, between approximately 200 mg and approximately 250 mg, between approximately 200 mg and approximately 260 mg, between approximately 200 mg and approximately 270 mg, between approximately 200 mg and approximately 280 mg, between approximately 200 mg and approximately 290 mg, between approximately 200 mg and approximately 300 mg, between approximately 200 mg and approximately 310 mg, between approximately 200 mg and approximately 320 mg, between approximately 200 mg and approximately 330 mg, between approximately 200 mg and approximately 340 mg, between approximately 200 mg and approximately 350 mg, between approximately 200 mg and approximately 360 mg, between approximately 200 mg and approximately 370 mg, between approximately 200 mg and approximately 380 mg,between approximately 200 mg and approximately 390 mg, between approximately 200 mg and approximately 400 mg, between approximately 200 mg and approximately 410 mg, between approximately 200 mg and approximately 420 mg, between approximately 200 mg and approximately 430 mg, between approximately 200 mg and approximately 440 mg, between approximately 200 mg and approximately 450 mg, between approximately 200 mg and approximately 460 mg, between approximately 200 mg and approximately 470 mg, between approximately 200 mg and approximately 480 mg, between approximately 200 mg and approximately 490 mg, between approximately 200 mg and approximately 500 mg, between approximately 200 mg and approximately 510 mg, between approximately 200 mg and approximately 520 mg, between approximately 200 mg and approximately 530 mg, between approximately 200 mg and approximately 540 mg, between approximately 200 mg and approximately 550 mg, between approximately 200 mg and approximately 560 mg,between approximately 200 mg and approximately 570 mg, between approximately 200 mg and approximately 580 mg, between approximately 200 mg and approximately 590 mg, between approximately 200 mg and approximately 600 mg, between approximately 200 mg and approximately 610 mg, between approximately 200 mg and approximately 620 mg, between approximately 200 mg and approximately 630 mg, between approximately 200 mg and approximately 640 mg, between approximately 200 mg and approximately 650 mg, between approximately 200 mg and approximately 660 mg, between approximately 200 mg and approximately 670 mg, between approximately 200 mg and approximately 680 mg, or between approximately 200 mg and approximately 690 mg per administration. In some aspects, the inositol phosphate dose of the present invention (e.g., myo-inositol hexaphosphate) is administered once daily (i.e., as a single daily dose). In some aspects, the daily dose can be subdivided into smaller doses and administered separately. Accordingly, in some aspects, the total daily dose can be subdivided into 2, 3, 4, or more subdoses (i.e., multiple daily doses). In some aspects, the inositol phosphate dosage of the present invention (e.g., myo-inositol hexaphosphate) is administered at least once a week. In some aspects, the inositol phosphate dosage of the present invention (e.g., myo-inositol hexaphosphate) is administered at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 times a week. In some aspects, the inositol phosphate dosage of the present invention (e.g., myo-inositol hexaphosphate) is administered for at least one week. In some aspects, the inositol phosphate dosage of the present invention is administered for approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 11 weeks. L 7 Rfrnn / Zznz / E / YIAI approximately 12 weeks f approximately 13 weeks approximately 14 weeks, approximately 15 weeks approximately 16 weeks, approximately 17 weeks approximately 18 weeks, approximately 19 weeks approximately 20 weeks f approximately 21 weeks approximately 22 weeks r approximately 23 weeks approximately 24 weeks r approximately 25 weeks approximately 26 weeks, approximately 27 weeks for 1 week to 12 weeks, for 1 week to 16 weeks, for 1 week to 20 weeks, for 1 week to 24 weeks, for 1 week to 28 weeks, for 1 week to 32 weeks, for 4 weeks to 8 weeks, for 4 weeks to 12 weeks, for 4 weeks to 16 weeks, for 4 weeks to 20 weeks, for 4 weeks to 24 weeks, for L 7 Rfrnn / Zznz / E / YIAI weeks to 28 weeks, for 4 weeks to 32 weeks, for 8 weeks to 12 weeks, for 8 weeks to 16 weeks, for 8 weeks to 20 weeks, for 8 weeks to 24 weeks, for 8 weeks to 28 weeks, for 8 weeks to ; 32 weeks, for 12 weeks to 16 weeks, for 12 weeks to 20 weeks, for 12 weeks to 24 weeks, for 12 weeks to 28 weeks, for 12 weeks to 32 weeks, for 16 weeks to 20 weeks, for 16 weeks to 24 weeks, for 16 weeks to 28 weeks, for 16 weeks to 32 weeks, for 20 weeks to 24 weeks, for 20 weeks to 28 weeks, for 20 weeks to 32 weeks, for 24 weeks to 28 weeks, for 24 weeks to 32 weeks, for 28 weeks to 32 weeks, for 32 weeks to 36 weeks, for 36 weeks to 40 weeks, weeks for or for 40 48 weeks weeks aaf 44 >2 weeks, weeks. For 44 to 48 weeks, in one particular aspect, the inositol phosphate dose of the present invention (for example, a dose of 300 mg or 600 mg of myo-inositol hexaphosphate) is administered 3 times a week. In particular, the inositol phosphate dose of the present invention (for example, a dose of 300 mg or 600 mg of myo-inositol hexaphosphate) is administered 3 times a week for at least 12 weeks, for at least 24 weeks, for at least 42 weeks, or for at least 52 weeks. Alternatively, the compound, pharmaceutical composition, or combination preparation may be administered as a component of a hemodialysis, hemofiltration, or peritoneal dialysis solution or system. In the specific case of patients undergoing dialysis, a highly suitable method of administration involves administering (for example, a non-bolus type) an inositol phosphate of the present invention through the dialysis machine (before or after the filter) instead of directly injecting the inositol phosphate of the present invention into the patient intravenously. Therefore, the blood can be treated with the inositol phosphate of the present invention (for example, myo-inositol hexaphosphate) as it leaves the patient and circulates through the dialysis circuit, and as the blood containing the inositol phosphate of the present invention returns to the body. Therefore, in some aspects, the compound, pharmaceutical composition, or combination preparation, as defined in any of the aspects disclosed above, is administered to a patient during hemodialysis. In some aspects, the compound, pharmaceutical composition, or combination preparation, as defined in any of the aspects disclosed above, is administered to the patient's blood drawn during hemodialysis, preferably before it is filtered (i.e., the therapeutic agent is administered to the patient's unfiltered blood in the dialysis circuit). In some aspects, the compound is inositol hexaphosphate, in particular, the sodium salt of myo-inositol hexaphosphate or a derivative thereof, specifically a compound of Formula I with R3 and R2 = radical of Formula V, where R13 is H and n is an integer from 2 to 200, and Ri, R5, R9, and Rn are all radicals of Formula II (or a sodium salt thereof). In the case of patients undergoing dialysis, the administration of an inositol phosphate of the present invention (e.g., myo-inositol hexaphosphate) through the dialysis machine allows the blood to equilibrate with the dialysis fluid before returning to the body; therefore, although the inositol phosphate of the present invention (e.g., myo-inositol hexaphosphate) may sequester ionic calcium, this is compensated for when the blood passes through the dialysis filter, thereby eliminating this side effect and significantly improving the safety profile.Additionally, the administration of the inositol phosphate of the present invention (e.g., myoinositol hexaphosphate) concomitant with hemodialysis, in particular when administered to the unfiltered blood extracted from the patient during hemodialysis, allows for a reduction in the dose of the compound with the consequent advantages in terms of reduced toxicity and minimization of adverse side effects. In some respects, the compound, pharmaceutical composition, or combination preparation, as defined in any of the above disclosed respects, is administered to a patient who is being treated with hemodialysis before dialysis treatment or after dialysis treatment. Instructions The compounds, pharmaceutical compositions, combination preparations, methods, and routes of administration, as defined in any of the aspects disclosed above, may be used for the treatment, inhibition of progression, or prevention of (a) cardiovascular calcification, or (b) a disease, condition, or symptom associated with cardiovascular calcification in a subject who requires it or (c) is at risk of developing such cardiovascular calcification, disease, condition, or associated symptom. In some aspects, the subject presents with renal insufficiency. In some additional aspects, the compounds, pharmaceutical compositions, combination preparations, methods and routes of administration, as defined in any of the aspects disclosed above, may be used for the treatment, inhibition of the progression or prevention of (a) coronary artery calcification, aortic artery calcification or aortic valve calcification, or (b) a disease, condition or symptom associated with coronary artery calcification, aortic artery calcification or aortic valve calcification in a subject who needs it or (c) at risk of developing coronary artery calcification, aortic artery calcification or aortic valve calcification or a disease, condition or symptom associated with any of the same.In some additional aspects, the pharmaceutical compositions of the invention comprise a combination preparation comprising at least one second active agent. In some aspects, the subject presents with renal insufficiency. In some cases, kidney disease in an individual may be acute, chronic, or both. In some cases, the individual undergoes dialysis (e.g., peritoneal or hemodialysis). In other cases, the individual undergoes hemodialysis. In still other cases, the individual does not undergo dialysis (e.g., an individual with CKD in stages 1 to 4). The following embodiments further illustrate the scope of the invention: Realization 1. A compound of General Formula I or a pharmaceutically acceptable salt thereof: L 7 Rfrnn / Zznz / E / YIAI And where: (i) Ri, R3, R5, R?, Rg and Rn are independently selected from OH, a radical of Formula II, III, IV and a heterologous residue: II III IV (ii) at least one of Ri, R3 Rs, R7, Rg and R11 is selected from a radical of Formula II, III and IV; and (iii) zero, one, two or three of Ri, R3, Rg, R· / , Rg and Rn is a heterologous residue; for use in the treatment, inhibition of progression or prevention of cardiovascular calcification or of a disease, condition or symptom associated with cardiovascular calcification in a subject in need thereof, wherein (a) the compound is in a form suitable for parenteral, topical or enteric administration and (b) the compound is administered to the subject in a non-bolus extended-release form in an effective dosage of approximately 200 mg to approximately 700 mg per administration. Realization 2. The compound according to realization 1, wherein the heterologous residue is selected from a radical of Formula V, a radical of Formula VI, and a radical of Formula VII: VII where n is an integer in the interval from 2 to 200 and R13 is selected from H, methyl and ethyl. Realization 3. The compound according to any one of realizations 1-2, wherein cardiovascular calcification is coronary artery calcification, aortic artery calcification, or aortic valve calcification. Realization 4. The compound according to any one of realizations 1-3, wherein the compound of Formula I is inositol hexaphosphate. Realization 5. The compound according to realization 4, wherein the inositol hexaphosphate is myo-inositol hexaphosphate. Embodiment 6. The compound according to any one of embodiments 4-5, wherein the inositol hexaphosphate is in its hexasodium salt form. Realization 7. The compound according to any one of realizations 1-3, wherein one or two of Ri, R3, R5, R7, Rg and R11 are selected from a radical of Formula V, VI and VII. Realization 8. The compound according to realization 7, wherein Ri, R5, Rg and R11 are a radical of Formula II and R3 and R? are a radical of Formula V. Realization 9. The compound according to realization 8, wherein the radical of Formula V has n in the range of 2 to 200 and R13 is H. Embodiment 10. A pharmaceutical composition for use in the treatment, inhibition of progression or prevention of cardiovascular calcification in a subject in need thereof comprising the compound according to any one of Embodiments 1-9 and pharmaceutically acceptable excipients and carriers. Realization 11. The composition according to any one of embodiments 1-9 or the pharmaceutical composition according to embodiment 10, wherein the subject presents with renal insufficiency. Realization 12. The composition according to any one of embodiments 1-9 or the pharmaceutical composition according to embodiment 10, wherein the subject undergoes dialysis. Embodiment 13. The compound or pharmaceutical composition according to any one of embodiments 1-12, wherein parenteral administration is by intravenous, subcutaneous, intramuscular or intravenous infusion. Embodiment 14. The compound or pharmaceutical composition according to Embodiment 13, wherein the intravenous infusion is administered using a dialysis machine. Realization 15. The compound or pharmaceutical composition according to any one of embodiments 1-14, wherein the subject is a human being. Embodiment 16. The compound or pharmaceutical composition according to any one of embodiments 1-15, wherein the compound is administered to the subject in a dosage of approximately 250 mg to approximately 650 mg per administration to the subject. Embodiment 17. The compound or pharmaceutical composition according to any one of embodiments 1-17, wherein the compound is administered to the subject in a dosage of approximately 300 mg to approximately 600 mg per administration to the subject. Embodiment 18. The compound or pharmaceutical composition according to any one of embodiments 1-17, wherein the compound is administered to the subject in a dosage of approximately 350 mg to approximately 550 mg per administration to the subject. Embodiment 19. The compound or pharmaceutical composition according to any one of embodiments 1-18, wherein the dosage is administered in single daily doses. Embodiment 20. The compound or pharmaceutical composition according to any one of embodiments 1-18, wherein the dosage is administered in multiple daily doses. Implementation 21. The compound or pharmaceutical composition according to any one of implementations 1-20, wherein the dosage is administered at least once a week. Implementation 22. The compound or pharmaceutical composition according to any one of implementations 1-21, wherein the dosage is administered 2, 3, 4, 5, 6 or 7 times a week. Embodiment 23. The compound or pharmaceutical composition according to any one of embodiments 1-22, wherein the dosage is administered for at least one week. Embodiment 24. The compound or pharmaceutical composition according to any one of embodiments 1-23, wherein the dosage is administered for approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, L 7 Rfrnn / Zznz / E / YIAI 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks. Implementation 25. The compound or pharmaceutical composition according to any one of implementations 1-24, wherein the dosage is administered for at least 12 weeks. Embodiment 26. The compound or pharmaceutical composition according to any one of embodiments 1-25, wherein the dosage is administered for at least 24 weeks. Embodiment 27. The compound or pharmaceutical composition according to any one of embodiments 1-26, wherein the dosage is administered for at least 42 weeks. Embodiment 28. The compound or pharmaceutical composition according to any one of embodiments 1-27, wherein the dosage is administered for at least 52 weeks. Embodiment 29. A combined preparation comprising (a) the compound according to any one of embodiments 1-9 or the pharmaceutical composition according to embodiment 10 and (b) at least one second active agent. Implementation 30. The combined preparation according to Implementation 29, wherein the second active agent is selected from the group consisting of a vitamin, a calcimimetic, a bisphosphonate, a phosphate binder, a thiosulfate, a pyrophosphate, a citrate, a diuretic, an antihypertensive, an anticholesterolemic agent, a phosphodiesterase inhibitor, and combinations thereof. Implementation 31. The combined preparation according to implementation 30, wherein the vitamin is vitamin B, vitamin D, vitamin K or a combination thereof. Implementation 32. The combined preparation according to Implementation 30, wherein the calcimimetic is cinacalcet ((R)-N-[1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-l-amine, KAI-4169 (etelcalcetide), NPS R-467 (((R)-N-(3-phenylpropyl)-l-(3-methoxyphenyl)ethylamine)), NPS R-568 ((R)-2-chloro-N-(1-(3-methoxyphenyl)ethyl)benzenepropanamine) or a combination thereof. Implementation 33. The combined preparation according to the L 7 Rfrnn / Zznz / E / YIAI embodiment 30, wherein the phosphate chelator is a calcium salt, an iron salt, a lanthanum salt, an aluminum salt, a magnesium salt, a sevelamer salt or a combination thereof. Implementation 34. The combined preparation according to implementation 30, wherein the bisphosphonate is etidronate, alendronate, risedronate, zoledronate, tiludronate, pamidronate, monidronate, neridronate, parnidronate, olpadronate, clodronate, ibandronate or a combination thereof. Implementation 35. The combined preparation according to Implementation 30, wherein the phosphodiesterase inhibitor is cilostazol, pentoxifylline, or a combination thereof. Embodiment 36. The combined preparation according to any one of embodiments 29-35, wherein (a) the compound according to any one of embodiments 1-9 or the pharmaceutical composition according to embodiment 10 and (b) the second active agent are administered separately, simultaneously or sequentially. The present invention is further illustrated by the following examples, which should not be construed as limiting. The content of all documents cited throughout this application is incorporated herein in its entirety by reference. Example 1 Slowing the progression of cardiovascular calcification with SNF472 in patients undergoing hemodialysis: results of a randomized phase 2b study The high cardiovascular morbidity and mortality in patients with end-stage renal disease (ESRD) may be partly due to extensive cardiovascular calcification (CVC). Intravenous myo-inositol hexaphosphate (SNF472) selectively inhibits hydroxyapatite formation and growth. In this double-blind, placebo-controlled, phase 2b trial, we compared changes in coronary artery calcium (CAC) volume score and other CVC measurements by CT scan over 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage renal disease (ESRD) undergoing hemodialysis. Patients were randomized 1:1:1 to receive either 300 mg of SNF472 (n=92), 600 mg of SNF472 (n=91), or placebo (n=91) via infusion into the hemodialysis lines three times weekly during hemodialysis sessions. The primary endpoint was the change in logarithmic CAC volume score from baseline to week 52.The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least one dose of SNF472 or placebo and underwent evaluable CT scans after baseline in the modified intention-to-treat (mITT) population. In the primary analysis, missing data were imputed using the last observation made (LOCF). The per-protocol analysis included all patients who underwent evaluable scans at week 52 and received 80% exposure to the study drug. The mean change in log-CAC volume score was 11% (95% CI, 7%–15%) in the SNF472 combination-dose group and 20% (95% CI, 14%–26%) in the placebo group (1^0.016) in the primary analysis (mITT with one LOCF).The mean change in logarithmic CAC volume score was 8% (95% CI, 4%-12%) in the SNF472 combined dose group and 24% (95% CI, 16-32%) in the placebo group (F=0.001) in a primary per-protocol (PP) analysis. SNF472, compared with placebo (mITT with one LOCF), significantly attenuated the evolution of the aortic valve calcium volume score (14% [95% CI, 5%-24%] vs. 98% [95% CI, 77%-123%], P<0.001). The median change from baseline in thoracic aortic volume score was 234 in the placebo group and 125 in the SNF472 combination-dose group. Death occurred in 7 patients (4%) receiving SNF472 and 5 patients (6%) receiving placebo. At least one treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with 300 mg SNF472, 600 mg SNF472, and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of 300 mg SNF472, 600 mg SNF472, and placebo in 14%, 29%, and 20% of patients, respectively. Therefore, compared with placebo, SNF472 significantly attenuated the progression of CAC and aortic valve calcification in patients with ESRD who received hemodialysis in addition to conventional care. Materials and methods Study design and participants A multinational, randomized, placebo-controlled, double-blind, phase 2b trial was conducted among adult patients (18 to 80 years of age) receiving hemodialysis for 6 months who had a coronary artery calcium (CAC) Agatston score between 100 and 3,500 units at baseline, as measured by a non-contrast multidetector computed tomography (MDCT) scanner. CAC Agatston scores were used for study eligibility because they are commonly used for risk stratification in clinical practice. Younger patients (18 to 54 years of age) were also required to have a history of diabetes mellitus (either type 1 or type 2).Key exclusion criteria were scheduled kidney transplantation, weight above 136 kg, recent hospitalization (within the last 3 months) for acute cardiovascular events (unstable angina, myocardial infarction, stroke, transient ischemic attack, amputation, peripheral or coronary surgical revascularization, or unstable heart failure), hypocalcemia (serum calcium <8.0 mg / dl [2.0 mmol / 1]), extreme elevation of serum phosphate (>10 mg / dl [3.23 mmol / 1] in the last 2 months), uncontrolled hypertension (2 or more consecutive post-dialysis diastolic blood pressure values ​​>100 mm Hg in the last 2 months), or a survival expectancy <2 years per investigator. After screening, eligible patients were randomized 1:1:1 to receive either 300 mg of SNF472, 600 mg of SNF472, or placebo 3 times a week, infused for 2.5 ± 0.5 hours at each hemodialysis session for 52 weeks. To maintain treatment concealment, randomization was performed using a centralized electronic randomization system, and the study drug was packaged in identical vials containing either SNF472 or physiological saline. Randomization was stratified according to baseline Agatston CAC score (100 to <399, 400 to 1,000, or >1,000 U). Investigators monitored blood pressure, calcium, phosphate, parathyroid hormone, lipids, and anemia according to current guidelines or standard practice at their institutions. At screening and at week 52 (or at the time of early discontinuation), coronary arteries, aortic valve, and thoracic aorta were imaged using MDCT, with a minimum of 64 slices. A central expert blinded to the patient's assigned treatment group reviewed each ultrasound scan and quantified each calcified area using both volume and the Agatston score (Callister T, et al., Radiology 1998; 208:807-814 and Agatston A, et al., J Am Coll Cardiol 1990; 15:827-832). A post-randomization ultrasound scan was considered evaluable if the expert image reviewer deemed it of sufficient quality to compare with the baseline ultrasound scan and could calculate a CAV volume score without being hindered by artifacts.Patients who discontinued treatment before week 52 without withdrawing consent were asked to undergo a CT scan for efficacy assessment in order to maximize follow-up and minimize missing data. Assessment criteria. The primary efficacy endpoint was the change from baseline to week 52 in the logarithmic CAC volume score, which has known lower variability than the Agatston score (Callister, 2008, cited above). The primary efficacy analysis combined the two SNF472 treatment groups compared with the placebo group. Secondary efficacy endpoints include change from baseline to week 52 in logarithmic CAC Agatston score and changes from baseline to week 52 in logarithmic calcium volume score and logarithmic calcium Agatston score at the level of the aortic valve and thoracic aorta and the proportion of patients with a <15% change in CAC Agatston score at week 52 (Budoff M, et al., JACC Cardiovasc Imaging 2010; 3:1229-1236).Each endpoint was analyzed in the combined SNF472 dose group compared with placebo and in each SNF472 dose group compared with placebo. Other endpoints included a composite safety endpoint for cardiovascular outcomes (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure), all-cause mortality, incidence of adverse events (generally serious or leading to discontinuation of the study drug), and changes from baseline to week 52 in clinical laboratory tests. Statistical analysis. Analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, North Carolina, USA). The safety population included all randomized patients who received at least one dose of SNF472 or placebo. The modified intention-to-treat (mITT) analysis population, used for efficacy analyses, consisted of all randomized patients who received at least one dose of SNF472 or placebo and a post-randomization CT scan with a CAC volume score. In the primary analyses of calcification evolution at week 52, the last observation (post-randomization ultrasound) performed (LOCF) in the mITT population was used. The primary efficacy analysis model was an analysis of covariance (ANCOVA) with the change in log score (log[week 52] - log[baseline]) as the dependent variable and a fixed-effects term for the randomized treatment group, as well as log(baseline), as covariates; the model was stratified according to the baseline Agatston CAC score. The primary comparison of interest was between the SNF472 combination dosing group and the placebo group; supporting comparisons examined differences between each dose and placebo. Least squares geometric means (LS) and 95% confidence intervals (CI) were calculated and re-transformed before submission to provide the mean percentage change from baseline to week 52. In each comparison between SNF472 and placebo, the geometric mean LS and 95% CI were calculated for treatment differences. Two-tailed p-values ​​<0.05 were considered statistically significant. For secondary efficacy endpoints, similar ANCOVA models were used to compare the NF472 combo dosing group versus placebo and the 300-mg and 600-mg SNF472 doses versus placebo individually. Null aortic valve and thoracic aorta calcium scores were imputed with the next smallest value in the relevant treatment arm. In the primary analyses of calcification evolution at week 52, the last observed calcification factor (LOCF) was used. In subsequent sensitivity analyses, multiple imputations were implemented to explore the effect of missing data in patients who discontinued the study early. If a patient had only a screening CAC volume score, no imputation was performed. In the first multiple imputation, missing data from each group were imputed using the distribution implied in the data of non-absent patients in that group. In the second multiple imputation, missing data from all groups were imputed using the distribution implied in the data of non-absent patients in the placebo arm. In the composite safety endpoint, proportional hazards (Cox) regression was used to compare SNF472 with placebo, stratified by the baseline Agatston CAC score. The planned sample size of 270 patients provided an 80% capacity to test the hypothesis that the true logarithmically transformed difference in evolution between the SNF472 combined dosage groups and the placebo group was 0.130, corresponding to an actual ratio of 1.139 or an evolution of 18.5%, in the case of the SNF472 combined dosage groups, and an evolution of 35%, in the case of the placebo group. Results Inclusion and disposition Of 645 patients from 65 centers who were screened for inclusion, 274 patients were randomized to one of three treatment groups: 300 mg of SNF472 (n=92), 600 mg of SNF472 (n=91), or placebo (n=91). The reasons for study discontinuation before week 52 were similar across all treatment groups. Safety assessments included 92, 91, and 90 patients, respectively, in the 300 mg SNF472, 600 mg SNF472, and placebo groups who received at least one dose of the study drug (Fig. 7). Follow-up CT scans for assessing changes in the calcium volume score in the mITT population were available in 142 patients in the SNF472 combination dosing groups and 77 patients in the placebo group. Baseline characteristics After the randomization code for this analysis was revealed, it was shown that the demographics and clinical characteristics of the patients at baseline were similar across the three treatment groups. At baseline, the geometric mean scores for the 300 mg SNF472, 600 mg SNF472, and placebo groups were 621, 636, and 634 units for the Agatston CAC scores, respectively, and 573, 583, and 584 for the CAC volume scores. The five baseline coronary artery and aortic valve calcium scores are summarized by treatment group in Table 1. Table 1 Baseline calcium scores (volume and Agatston) Placebo (n=77) 300 mg of SNF472 (n=77) 600 mg of SNF472 (n=65) Coronary artery calcium score Volume 58410.88 57310.83 58310.89 Agatston score, 63410.96 62110.91 63610.98 units Aortic valve calcium score Volume 15.311.94 27.912.04 15.511.90 Agatston score, 8.112.47 17.512.56 8.512.44 units Thoracic aorta calcium score Volume 113811.82 109511.87 98111.91 Agatston's score, 127612.00 121012.08 109612.14 units Data are expressed as a geometric mean 1 log (DT) in the modified intention-to-treat population. Coronary arteries In the primary endpoint, SNF472 (groups of 15 combined dosing) significantly attenuated the evolution of CAC compared with placebo: the mean change in CAC volume score from baseline to week 52 was 11% (95% CI, 7%-15%) and 20% (95% CI, 14%-26%), respectively (P=0.016; Fig. 8A). The mean change from baseline to week 52 in CAC volume score was 12% (95% CI, 6%-18%) in the 300 mg dose group (P=0.052 compared to placebo), and 10% (95% CI, 4%-17%) in the 600 mg dose group (P=0.029 compared to placebo) (Fig. 11A). The corresponding results using the Agatston score for CAC were a mean change of 11% (95% CI, 6%-17%) for the SNF472 combination dosing groups, and % (95% CI, 12%-28%) for the placebo group (P=0.075; Fig. 8B). The mean change in the Agatston CAC score was % (95% CI, 3%-17%) for the 300 mg dose group (F=0.055 compared to placebo), and 13% (95% CI, 6%-22%) for the 600 mg dose group (P=0.24 compared to placebo) (Fig. 11B). Somewhat better results were obtained for the evolution of calcium volume and Agatston scores in the per-protocol population of patients who completed 52 weeks of treatment (Fig. 9A and 9B) and in sensitivity analyses that used multiple imputation of missing data in the mITT population (Fig. 12A and 12B). The proportion of patients with a change of <15% in the Agatston CAC score at week 52 was 61% in the SNF472 combination dosing group and 48% in the placebo group in the mITT population (1^0.030; Fig. 10A), and 64% and 43%, respectively, in the per-protocol population (P=0.002; Fig. 10B). Aortic valve The changes from baseline to week 52 in aortic valve calcium volume scores were 14% (95% CI, 5%–24%) in the SNF472 combination dosing groups and 98% (95% CI, 77%–123%) in the placebo group (P<0.001; Fig. 8C). The mean change from baseline to week 52 was 28% (95% CI, 14%–43%) in the 300-mg dose group (P<0.001 compared with placebo) and 1% (95% CI, -10%–14%) in the 600-mg dose group (P<0.001 compared with placebo) (Fig. 11C). The corresponding results for Agatston calcium scores were 14% (95% CI, 2%-28%) in the SNF472 combination dosing groups and 186% (95% CI, 145%-235%) in the placebo group (P<0.001; Fig. 8D). The mean change from baseline to week 52 was 33% (95% CI, 14%-54%) in the 300 mg dose group (P<0.001 compared with placebo) and -2% (95% CI, -16%-16%) in the 600 mg dose group (P<0.001 compared with placebo) (Fig. 11D). Similar results were obtained for the evolution of calcium volume and Agatston scores in sensitivity analyses using multiple imputation of missing data in the mITT population (Fig. 12C and 12D). Thoracic aorta The changes from baseline to week 52 in thoracic aortic calcium volume scores were 23% (95% CI, 16%–30%) in the SNF472 combination dosing groups and 28% (95% CI, 19%–38%) in the placebo group (P=0.40; Fig. 8E). The mean change from baseline to week 52 was 25% (95% CI, 16%–35%) in the 300-mg dose group (P=0.63 compared with placebo) and 21% (95% CI, 11%–32%) in the 600-mg dose group (P=0.34 compared with placebo) (Fig. HE). The corresponding Agatston calcium scores were 29% (95% CI, 20%–38%) in the SNF472 combination dosing groups and 32% (95% CI, 21%–45%) in the placebo group (P=0.66; Fig. 8F). The mean change from baseline to week 52 was 30% (95% CI, 19%–43%) in the 300-mg dose group (P=0.82 compared with placebo) and 28% (95% CI, 15%–42%) in the 600-mg dose group (F=0.61 compared with placebo) (Fig. 11F). Similar results were obtained in the evolution of calcium volume and Agatston scores in the sensitivity analyses that used multiple imputation of missing data in the mITT population (Fig. 12E and 12F). The median change from baseline in thoracic aortic volume score was 204 in the placebo group and 131 in the SNF472 combined-dose group (mITT with one LOCF), representing a difference of 35.8%. The median change from baseline in thoracic aortic volume score was 234 in the placebo group and 125 in the SNF472 combined-dose group (PP), representing a difference of 46.6%. Composite safety endpoint The incidence of the composite safety endpoint in the 300 mg SNF472, 600 mg SNF472, and placebo groups was 8%, 7%, and 11%, respectively (Table 2). The hazard ratio for the composite safety endpoint in the SNF472 combination dosing groups compared with placebo was 0.60 (95% CI, 0.26–1.37; P = 0.22). Table 2 Composite safety assessment criteria Placebo (n= 9 0) 300 mg of SNF472 600 mg of SNF472 (ir = 92) (ir = 91) Any event of the composite safety endpoint (11,1) 10 7 1 A, 6) 6 ( :6,6) Death from cardiovascular causes 0 0 1 ( :i,d Non-fatal myocardial infarction 4 (4,4) 4 ( :4,3) 1 1 :i,d Non-fatal stroke 2 (2,2) 1 1 ;i,d 0 Heart failure 4 (4,4) 1 ( :i,d 2 ( :2,2) Non-fatal cardiac arrest 0 1 ( :i, i) 2 ( :2,2) The data is expressed as a number (%). Adverse events Adverse events occurred in 79 of 92 patients (86%) in the SNF472 300 mg group, in 84 of 91 patients (92%) in the SNF472 600 mg group, and in 78 of 90 patients (87%) in the placebo group. Serious adverse events occurred in 38 patients (41%) in the SNF472 300 mg group, in 55 patients (60%) in the SNF472 600 mg group, and in 49 patients (54%) in the placebo group. Adverse events led to drug withdrawal from the study in 13 patients (14%) in the 300 mg SNF472 group, in 26 patients (29%) in the 600 mg SNF472 group, and in 18 patients (20%) in the placebo group. Most of these study discontinuations were due to kidney transplantation in 27 patients overall (6% of the 300 mg SNF472 group, 12% of the 600 mg SNF472 group, and 9% of the placebo group). No other event led to drug withdrawal from the study in more than two patients. No clinically significant abnormalities were identified from the analysis of clinical laboratory values ​​(hematology and chemistry) with SNF472 compared to placebo. Death occurred in one patient in the 300 mg SNF472 group (multiple organ dysfunction syndrome), in six patients in the 600 mg SNF472 group (one in each group due to aortic stenosis, arteriosclerosis, hypotension, cardiac arrest, septic shock, and epilepsy), and in five patients in the placebo group (one in each group due to congestive heart failure, multiple organ dysfunction syndrome, sepsis, post-procedure complication, and kidney transplantation). None of the deaths were considered related to the study drug. Analysis This multinational, multicenter, randomized, double-blind, placebo-controlled clinical trial showed that SNF472, a selective inhibitor of hydroxyapatite crystal formation and growth, when infused at each hemodialysis session for one year, attenuated the progression of coronary artery and aortic valve calcification relative to placebo. These results are surprising in view of the concomitant use of drugs that have been shown in previous studies to potentially attenuate CAC, such as the non-calcium-based phosphate binder sevelamer and the calcimimetic cinacalcet (Raggi P, et al., Nephrol Dial Transplant. 2011; 26:1327-1339, Chertow G, et al., Kidney Int. 2002; 62:245-2352 and Sadek T, et al., Nephrol Dial Transplant. 2003; 18:582588).In previous studies, hemodialysis patients assigned to placebo showed an average CAC evolution rate of 35–40% per year, almost twice the evolution rate observed in placebo-treated patients in this study. Interestingly, the study's capacity calculations assumed an evolution of CAC volume score of 18.5% for SNF472-treated patients and 35% for placebo-treated patients (a relative evolution difference of 47%). These assumptions were based on previously published evolution rates. Although the observed CAC evolution in placebo-treated patients in this study was slower than expected, partly due to the use of non-calcium-based phosphate binders and calcimimetics in many patients, the relative difference of 45% was very close to the study's initial expectations. At baseline, all patients had coronary calcium with Agatston CAC scores ranging from 100 to 3,500 units. Additionally, 57% of patients had aortic valve calcification (Bellasi, 2019, cited above). Since the primary objective of the study was to demonstrate that SNF472 effectively inhibits the progression of coronary calcification, patients with moderate to high CAC scores were included, as these patients generally exhibit more rapid calcification progression. Previous meta-analyses have shown that prescribing non-calcium-based phosphate binders is associated with attenuating the progression of cardiovascular calcification, as well as with improved survival (Jamal S, et al., Lancet 2013; 382:1268-1277 and Patel L, et al., Clin J Am Soc Nephrol. 2016; 11:232-244). The association between cardiovascular calcification and morbidity and mortality has been demonstrated in the general population in numerous previous publications. As a result, cardiovascular calcification (CAC) has been recognized as a risk-modifying marker in the most recent American Heart Association and American College of Cardiology guidelines for the primary prevention of atherosclerotic cardiovascular disease.Furthermore, both the CAC measured on CT and simple measures of calcification, such as radial and femoral artery calcification, as well as aortic calcification observed on planar radiographs, have been shown to be strongly associated with adverse events in ERT (Blacher J, et al., Hypertension 2001; 38:938-942, Adragao T, et al., Nephrol Dial Transplant. 2009; 24:997-1002, Disthabanchong S, et al., Int Urol Nephrol. 2018; 50:355-364, Kwon H, et al., Kidney Res Clin Pract. 2014; 33:95-102, Okuno S, et al., Am J. Kidney Dis. 2007; 49:417-425 and Verbeke F, et al., Clin J Am Soc Nephrol. 2011; 6:153-159). It is well established that patients with end-stage renal disease (ESRD) develop cardiovascular calcifications at a much higher rate than patients with normal or near-normal renal function, and that there are two distinct sites of arterial calcification in these patients: intima and media. The former is related to traditional risk factors for atherosclerosis and inflammation, while the latter is found primarily (if not exclusively) in medium- and large-diameter arteries and is more closely associated with the mineral and bone disorder typical of ESRD. Calcification of the medium- and large-diastolic conduits is responsible for reduced vascular distensibility, which can induce left ventricular hypertrophy and long-term systolic / diastolic dysfunction.Reduced compliance, as measured by increased pulse pressure velocity, can result in reduced diastolic filling of the coronary arteries with a state of relative myocardial ischemia even in the absence of obstructive luminal disease. Therefore, arterial calcification in ESRD should be interpreted as a harbinger of serious complications and is thus worth pursuing as a therapeutic target. Equally important is the impact of valvular calcification in ESRD, particularly aortic valve calcification (Marwick T, et al., Kidney Int. 2019; 96:836-849). Many patients suffer from severe calcification of the left-sided heart valves with valvular regurgitation or posterior restriction of valve leaflet mobility.These conditions are associated with progressive left ventricular fibrosis, left ventricular hypertrophy and dysfunction, as well as endocarditis and serious conduction abnormalities. Furthermore, surgical and interventional treatments that have proven effective in the general population may not provide a similar benefit in patients with end-stage renal disease. Therefore, the significant reduction in the progression of aortic valve calcification observed in this study is encouraging. Regardless of the pathophysiology of cardiovascular calcification, the final stage involves the formation of hydroxyapatite crystals through active processes that mimic bone assembly. In this regard, SNF472 is a specific inhibitor of hydroxyapatite crystallization and is effective in slowing the progression of calcification in the coronary arteries and aortic valve. Conclusions Compared with placebo, 52 weeks of treatment with SNF472 significantly attenuated the progression of coronary artery and aortic valve calcification in patients with end-stage renal disease (ESRD) undergoing hemodialysis. These results were obtained in a context of frequent use of drugs capable of at least partially attenuating the progression of cardiovascular calcification in ESRD patients.

Claims

1. A compound of general Formula I or a pharmaceutically acceptable salt thereof: wherein: (i) Ri, R3, R5, R7, Rg and Rn are independently selected from OH, a radical of Formula II, III, IV and a heterologous moiety: II III IV (ii) at least one of Ri, R3, Rs, R7, Rg and Ru is selected from a radical of Formula II, III and IV; and (iii) zero, one, two or three of Ri, R3, Rs, R7, Rg and R11 is a heterologous moiety; for use in the treatment, inhibition of progression or prevention of cardiovascular calcification or of a disease, condition or symptom associated with cardiovascular calcification in a subject in need thereof, wherein (a) the compound is in a form suitable for parenteral, topical or enteric administration and (b) the compound is administered to the subject in a non-bolus extended-release form in an effective dosage of approximately 200 mg to approximately 700 mg per administration.

2. The compound according to claim 1, wherein the heterologous moiety is selected from a radical of Formula V, a radical of Formula VI and a radical of Formula VII: VII wherein: n is an integer in the range of 2 to 200, and Ría is selected from H, methyl and ethyl.

3. The compound according to any one of claims 1-2, wherein cardiovascular calcification is coronary artery calcification, aortic artery calcification or aortic valve calcification.

4. The compound according to any one of claims 1-3, wherein the compound of Formula I is inositol hexaphosphate.

5. The compound according to claim 4, wherein the inositol hexaphosphate is myo-inositol hexaphosphate.

6. The compound according to any one of claims 4-5, wherein the inositol hexaphosphate is in its hexasodium salt form.

7. The compound according to any one of claims 1-3, wherein one or two of Ri, R3, R5, R7, Rg and Rn are selected from a radical of Formula V, VI and VII.

8. The compound according to claim 7, wherein Ri, R5, Rg and Rn are a radical of Formula II and R3 and R? are a radical of Formula V.

9. The compound according to claim 8, wherein the radical of Formula V has n in the range of 2 to 200 and R13 is H.

10. A pharmaceutical composition for use in the treatment, inhibition of progression or prevention of cardiovascular calcification in a subject in need thereof comprising the compound according to any one of claims 1-9 and pharmaceutically acceptable excipients and carriers.

11. A pharmaceutical composition for use in the treatment, inhibition of progression or prevention of cardiovascular calcification in a subject in need, comprising myo-inositol hexaphosphate and pharmaceutically acceptable excipients and vehicles.

12. The compound according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 10-11, wherein the subject has renal insufficiency.

13. The compound according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 10-11, wherein the subject undergoes dialysis.

14. The compound or pharmaceutical composition according to any one of claims 1-13, wherein parenteral administration is by intravenous, subcutaneous, intramuscular or intravenous infusion.

15. The compound or pharmaceutical composition according to claim 14, wherein the intravenous infusion is administered using a dialysis apparatus.

16. The compound or pharmaceutical composition according to any one of claims 1-15, wherein the subject is a human being.

17. The compound or pharmaceutical composition according to any one of claims 1-16, wherein the compound is administered to the subject in a dosage of approximately 250 mg to approximately 650 mg per administration to the subject.

18. The compound or pharmaceutical composition according to any one of claims 1-17, wherein the compound is administered to the subject in a dosage of approximately 300 mg to approximately 600 mg per administration to the subject.

19. The compound or pharmaceutical composition according to any one of claims 1-18, wherein the compound is administered to the subject in a dosage of approximately 350 mg to 550 mg per administration to the subject.

20. The compound or pharmaceutical composition according to any one of claims 1-19, wherein the dosage is administered in single daily doses.

21. The compound or pharmaceutical composition according to any one of claims 1-20, wherein the dosage is administered in multiple daily doses.

22. The compound or pharmaceutical composition according to any one of claims 1-21, wherein the dosage is administered at least once a week.

23. The compound or pharmaceutical composition according to any one of claims 1-22, wherein the dosage is administered 2, 3, 4, 5, 6 or 7 times a week.

24. The compound or pharmaceutical composition according to any one of claims 1-23, wherein the dosage is administered for at least one week.

25. The compound or pharmaceutical composition according to any one of claims 1-24, wherein the dosage is administered for approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks.

26. A combined preparation comprising (a) the compound according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 1011 and (b) at least one second active agent.