Inositol phosphate compounds for use in treating, inhibiting the progression of, or preventing cardiovascular calcification

Abstract

The present invention relates to compounds, pharmaceutical compositions, combination formulations, and administration regimens containing inositol phosphates for treating, inhibiting the progression of, and preventing cardiovascular calcification, particularly coronary artery calcification, aortic calcification, and aortic valve calcification. In a detailed aspect, the present disclosure provides an administration regimen for treating, inhibiting the progression of, or preventing cardiovascular calcification, comprising administration of about 200 mg to about 700 mg of myo-inositol hexaphosphate per administration.

Description

[Technical Field]

[0001] The present invention relates to the use of inositol phosphates (IPs), their analogs and derivatives for treating, inhibiting the progression of, or preventing cardiovascular calcification in human health. The present invention also relates to pharmaceutical compositions and combination formulations comprising said IPs and dosage regimens for their administration. [Background technology]

[0002] The relative risk of death from cardiovascular causes is 5 to 30 times higher in patients with end-stage renal disease (ESKD) requiring dialysis than in the general population (Foley R et al., Am J Kidney Dis. 1998;32:S112-119). Traditional risk factors, such as diabetes and hypertension, are highly prevalent in patients with chronic kidney disease (CKD), but they only account for a portion of the increased cardiovascular risk (Cozzolino M et al., Nephrol Dial Transplant. 2018;33:iii28-iii34). In clinical practice, at least 80% of patients undergoing maintenance hemodialysis have evidence of cardiovascular calcification (Raggi P et al., J Am Coll Cardiol. 2002;39:695-701 and Bellasi A et al., Kidney Int. 2006;70:1623-1628). This marker of vasculopathy is associated with morbidity and mortality in the general population and in patients undergoing maintenance hemodialysis (Blaha M et al., Lancet 2011;378:684-6 and Chen J et al., JAMA Cardiol. 2017;2:635-643).

[0003] In patients with advanced CKD, cardiovascular calcification may be secondary to a combination of rapidly progressive atherosclerosis, and is more likely to be secondary to arteriosclerosis related to disturbances in mineral metabolism (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 similar to bone formation, ultimately dependent on HAP nucleation and crystal growth. Patients with CKD and cardiovascular calcification experience 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; 13:210-220; Raggi P et al., Kidney Int. 2007; 71:802-807; Di Iorio 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 Nucl Cardiol. 2013; 20:1013-1020).

[0004] There is evidence that attenuation of vascular calcification progression in CKD is associated with reduced mortality (Jamal S et al., Lancet 2013;382:1268-1277). The phosphate binder sevelamer and the calcimimetic drug cinacalcet, used to treat hyperphosphatemia and secondary hyperparathyroidism, respectively, may slow the progression of vascular calcification in ESKD. However, these drugs do not adequately address the complex biology underlying 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).

[0005] SNF472, a formulation of myo-inositol hexaphosphate, acts through a novel pathway that selectively and directly inhibits the formation and growth of HAP crystals, a common final step 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). By infusing SNF472 during each dialysis session, therapeutic levels are achieved, ensuring treatment adherence without additional patient burden (Perello J et al., J Nephrol. 2018;31:287-296). A phase 1 clinical trial showed that a single dose of SNF472 at 9 mg / kg inhibited HAP crystallization potential by 80% compared to 9% with placebo in patients undergoing maintenance hemodialysis (Perello J et al., Br J Clin Pharmacol. 2018;84:2867-2876). Therefore, SNF472 may be a candidate for attenuating the progression of cardiovascular calcification in dialysis patients. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Foley R et al., Am J Kidney Dis. 1998;32:S112-119 Summary of the Invention [Means for solving the problem]

[0007] In a first aspect, the present invention provides a compound of general formula I, or a pharmaceutically acceptable salt thereof, for use in treating, inhibiting the progression of, or preventing cardiovascular calcification, or a disease, condition, or symptom associated with cardiovascular calcification, in a subject in need thereof.

[0008] [ka]

[0009] [In the formula, (i)R 1、 R 3、 R 5、 R 7、 R9 and R 11 are independently selected from OH, groups of formula II, III, IV:

[0010] [ka]

[0011] and a heterologous moiety, (ii) R1, R3, R5, R7, R9 and R 11 at least one of which is selected from groups of formula II, III and IV, (iii)R 1、 R 3、 R 5、 R 7、 R9 and R 11 wherein 0, 1, 2 or 3 are heterologous moieties; (a) the compound is in a form suitable for parenteral, topical, or enteral administration; and (b) the compound is administered to a subject in a non-bolus sustained release form at an effective dose of about 200 mg to about 700 mg per dose.

[0012] In some embodiments, the present invention relates to compounds of general formula I, as defined above, wherein the heterologous moiety is a group of formula V, a group of formula VI, and a group of formula VII:

[0013] [ka]

[0014] n is an integer ranging from 2 to 200; R 13 is selected from H, methyl or ethyl. Alternatively, the present invention relates to a compound of general formula I, as defined above, for use in treating, inhibiting the progression of, or preventing cardiovascular calcification in a subject in need thereof, wherein: (a) the compound is in a form suitable for parenteral, topical, or enteral administration; (b) the compound is administered to the subject in a non-bolus sustained-release form at a dosage of about 200 mg to about 700 mg per administration; and (c) administration of the compound treats, inhibits the progression of, or prevents cardiovascular calcification, or a disease, condition, or symptom associated with cardiovascular calcification, in the subject.

[0015] In a further aspect, the present invention also relates to a method for treating, inhibiting the progression of, or preventing cardiovascular calcification, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, as defined above, together with a pharmaceutically acceptable excipient or carrier. This aspect can also be envisaged 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 cardiovascular calcification in a subject in need thereof.

[0016] In another aspect, the present invention also relates to a method for treating, inhibiting the progression of, or preventing coronary artery calcification, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, as defined above, together with a pharmaceutically acceptable excipient or carrier. This aspect can also be envisaged 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 thereof.

[0017] In a further aspect, the present invention relates to a method for treating, inhibiting the progression of, or preventing aortic calcification, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, as defined above, together with a pharmaceutically acceptable excipient or carrier. This aspect can also be envisioned 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 thereof.

[0018] In a further aspect, the present invention relates to a method for treating, inhibiting the progression of, or preventing aortic valve calcification, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, as defined above, together with a pharmaceutically acceptable excipient or carrier. This aspect can also be envisioned 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 valve calcification in a subject in need thereof.

[0019] The compounds of the present invention are particularly useful for treating, inhibiting the progression of, or preventing coronary artery calcification, aortic calcification, and / or aortic valve calcification in dialysis patients, particularly in dialysis patients with renal failure.

[0020] The present invention also provides a pharmaceutical composition comprising at least one compound of formula I, as defined above, for use in (i) treating, inhibiting the progression of, or preventing cardiovascular calcification, (ii) treating, inhibiting the progression of, or preventing coronary artery calcification, (iii) treating, inhibiting the progression of, or preventing aortic calcification, and / or (iii) or treating, inhibiting the progression of, or preventing aortic valve calcification in a subject in need thereof.

[0021] In a further aspect, the present invention relates to a combined preparation comprising at least one compound of formula I or a pharmaceutical composition according to the present invention and at least one second active agent, and to the use of said combined preparation in human health, in particular in dialysis patients with renal failure. [Brief explanation of the drawings]

[0022] [Figure 1] Figure 1 shows a representative inositol phosphate analogue in which two of the six Xs are OPSO2 2- and the remaining X is OSO3. Four specific forms of 4,6-di-(O-thiophosphate)-inositol-1,2,3,5-tetra-O-sulfate are shown. [Figure 2]

[0023] Figure 1 shows inositol phosphate analogs and derivatives that can be used to carry out the methods of the invention. The molecules shown are myo-inositol-pentaphosphate-2-PEG400, myo-inositol hexakissulfate, and scyllo-myo-inositol hexakissulfate. [Figure 3] 1 shows inositol phosphate analogs and derivatives that can be used to practice the methods of the invention. X independently represents a phosphorus- and / or sulfur-containing group (e.g., phosphate, sulfate, or thiophosphate). R represents a heterologous moiety (e.g., PEG or PG). [Figure 4] 1 shows exemplary inositol phosphate analogs and derivatives that can be used to practice the methods of the invention. R1 represents a heterologous moiety (e.g., PEG or PG). n can be 2 to 200. [Figure 5] 1 shows exemplary inositol phosphate analogs and derivatives that can be used to practice the methods of the present invention. n can be from 2 to 200. [Figure 6] 1 shows exemplary inositol phosphate analogs and derivatives that can be used to practice the methods of the present invention. n can be from 2 to 200. [Figure 7] Diagram illustrating patient disposition in the clinical trial. 231 patients did not have a coronary artery calcium score within the required range at screening (*). Other reasons for patient exclusion included having a computed tomography scan completed or evaluable, not having a kidney transplant, or having completed screening / enrollment (†). [Figure 8A] Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention to treat (mITT) population with last observation carried forward (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 8B]Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention to treat (mITT) population with last observation carried forward (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 8C] Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention to treat (mITT) population with last observation carried forward (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 8D] Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention to treat (mITT) population with last observation carried forward (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 8E] Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention to treat (mITT) population with last observation carried forward (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 8F]Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention to treat (mITT) population with last observation carried forward (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 9A] Figure 1 shows calcium volume progression and Agatston score obtained in the per-protocol (PP) population of patients who completed week 52 of treatment. A, Coronary calcium volume. B, Coronary Agatston score. [Figure 9B] Figure 1 shows calcium volume progression and Agatston score obtained in the per-protocol (PP) population of patients who completed week 52 of treatment. A, Coronary calcium volume. B, Coronary Agatston score. [Figure 10A] 1 shows the proportion of patients with <15% progression in CAC Agatston score at week 52. A, mITT population; B, PP population. [Figure 10B] 1 shows the proportion of patients with <15% progression in CAC Agatston score at week 52. A, mITT population; B, PP population. [Figure 11A] Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination and individual dosing groups vs. placebo. Modified intention-to-treat population (mITT) with long-term until last observation (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 11B]Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination and individual dosing groups vs. placebo. Modified intention-to-treat population (mITT) with long-term until last observation (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 11C] Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination and individual dosing groups vs. placebo. Modified intention-to-treat population (mITT) with long-term until last observation (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 11D] Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination and individual dosing groups vs. placebo. Modified intention-to-treat population (mITT) with long-term until last observation (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 11E] Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination and individual dosing groups vs. placebo. Modified intention-to-treat population (mITT) with long-term until last observation (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 11F]Figure 1 shows the mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination and individual dosing groups vs. placebo. Modified intention-to-treat population (mITT) with long-term until last observation (LOCF). A, Coronary artery calcium volume. B, Coronary artery Agatston score. C, Aortic valve calcium volume. D, Aortic valve Agatston score. E, Thoracic aorta calcium volume. F, Thoracic aorta Agatston score. [Figure 12A] Figure 1 shows the mean of sensitivity analysis of mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention-to-treat (mITT) population by multiple imputation. A, Coronary artery calcium volume score. B, Coronary artery calcium Agatston score. C, Aortic valve calcium volume score. D, Aortic valve calcium Agatston score. E, Thoracic aorta calcium volume score. F, Thoracic aorta calcium Agatston score. [Figure 12B] Figure 1 shows the mean of sensitivity analysis of mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention-to-treat (mITT) population by multiple imputation. A, Coronary artery calcium volume score. B, Coronary artery calcium Agatston score. C, Aortic valve calcium volume score. D, Aortic valve calcium Agatston score. E, Thoracic aorta calcium volume score. F, Thoracic aorta calcium Agatston score. [Figure 12C] Figure 1 shows the mean of sensitivity analysis of mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention-to-treat (mITT) population by multiple imputation. A, Coronary artery calcium volume score. B, Coronary artery calcium Agatston score. C, Aortic valve calcium volume score. D, Aortic valve calcium Agatston score. E, Thoracic aorta calcium volume score. F, Thoracic aorta calcium Agatston score. [Figure 12D]Figure 1 shows the mean of sensitivity analysis of mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention-to-treat (mITT) population by multiple imputation. A, Coronary artery calcium volume score. B, Coronary artery calcium Agatston score. C, Aortic valve calcium volume score. D, Aortic valve calcium Agatston score. E, Thoracic aorta calcium volume score. F, Thoracic aorta calcium Agatston score. [Figure 12E] Figure 1 shows the mean of sensitivity analysis of mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention-to-treat (mITT) population by multiple imputation. A, Coronary artery calcium volume score. B, Coronary artery calcium Agatston score. C, Aortic valve calcium volume score. D, Aortic valve calcium Agatston score. E, Thoracic aorta calcium volume score. F, Thoracic aorta calcium Agatston score. [Figure 12F] Figure 1 shows the mean of sensitivity analysis of mean (95% CI) change from baseline to week 52 for calcium scores in the SNF472 combination dosing group vs. placebo. Modified intention-to-treat (mITT) population by multiple imputation. A, Coronary artery calcium volume score. B, Coronary artery calcium Agatston score. C, Aortic valve calcium volume score. D, Aortic valve calcium Agatston score. E, Thoracic aorta calcium volume score. F, Thoracic aorta calcium Agatston score. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention provides compounds, pharmaceutical compositions, combination formulations, methods, and routes of administration for use in treating, inhibiting the progression of, or preventing cardiovascular calcification. The present invention also provides compounds, pharmaceutical compositions, methods, and routes of administration for use in treating, inhibiting the progression of, or preventing coronary artery calcification, aortic calcification, and / or aortic valve calcification.

[0024] The compounds, pharmaceutical compositions, combination formulations, methods and routes of administration of the present invention are particularly useful for treating, inhibiting the progression of, or preventing coronary artery calcification, aortic calcification and / or aortic valve calcification in dialysis patients, more particularly in dialysis patients with renal failure.

[0025] Definitions of common terms and expressions The invention includes embodiments in which only one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention also includes embodiments in which more than one, or all, of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this description relates.For example, Pei-Show J, Concise Dictionary of Biomedicine and Molecular Biology, 2nd edition (CRC Press, Boca Raton, FL, USA 2002); Lackie J, The Dictionary of Cell and Molecular Biology, 5th edition (Academic Press, Cambridge, MA, USA 2013) and Cammack R et al., Oxford Dictionary of Biochemistry and Molecular Biology, 2nd edition (Oxford University Press, Oxford, GB, 2006) provide those skilled in the art with a general dictionary that includes many of the terms used in this description.

[0027] Units, prefixes, and symbols are shown in the form recognized by their International System of Units (SI). Numerical ranges are inclusive of the numbers defining the range. When a range of values ​​is recited, it is understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range, along with each subrange between such values, is also specifically disclosed. The upper and lower limits of any range may independently be included or excluded from the range, and each range with either limit included, neither limit included, or both limits included, is also encompassed within the scope of the invention.

[0028] When values ​​are explicitly recited, it is to be understood that values ​​that are about the same content or amount as the recited value are also within the scope of the invention. Where 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, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of an invention is disclosed as having multiple alternatives of that invention, and each alternative individually excluded or in any combination with other alternatives is also disclosed herein; more than one element of an invention can have such an exclusion, and all combinations of elements with such exclusion are disclosed herein.

[0029] As used herein, the term "and / or" is to be construed as a specific disclosure of each of the two specified features or components, with or without the other. Thus, the term "and / or" used herein in the form of a phrase such as "A and / or B" is intended to include "A and B," "A or B," "A" (single), and "B" (single). Similarly, the term "and / or" used in the form of a phrase such as "A, B, and / or C" is intended to encompass each of the following embodiments: 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 (single); B (single); and C (single).

[0030] As used herein, the term "aortic calcification" refers to the formation of calcific deposits in the aorta. Types of aortic calcification include, but are not limited to, calcification of the abdominal and thoracic aorta and the common external and internal iliac arteries (e.g., femoral, lateral sacral). As used herein, the term "aortic valve calcification" refers to the formation of calcific deposits in the aortic valve. Calcification of the aortic valve can result in narrowing of the aortic valve, a condition defined as aortic valve stenosis or "AVS." Blood flow from the heart can be reduced by AVS, resulting in overwork and weakness of the heart muscle.

[0031] As used herein and as applied to one or more values ​​of interest, the term "approximately" refers to a value similar to a specified reference value. In some embodiments, the term "approximately" refers to a range of values ​​that is 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or less than) the specified reference value, unless otherwise stated or apparent from the context (except where such number exceeds 100% of the possible values).

[0032] As used herein, the term "cardiovascular calcification" and its related term "CVC" refer to the formation of calcification in cardiac blood vessels. Calcification can occur in the intimal (inner) or intermediate (middle) portions of blood vessels. 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 calcification, aortic valve calcification) include, but are not limited to, angina pectoris, aneurysm, atherosclerosis (e.g., coronary artery calcification), arteriosclerosis, arteriosclerosis, heart disease, cerebrovascular disease, coronary disease, electrocardiogram abnormalities, heart failure, congestive heart failure, hypertension, left ventricular hypertrophy, myocardial infarction, myocardial ischemia, peripheral arterial disease, peripheral vascular disease, and thrombosis.

[0033] As used herein, the term "compound" is meant to include all isomers and isotopes of the depicted structures. As used herein, the term "isomer" refers to any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer, or diastereomer of a compound. A compound may contain one or more chiral centers and / or double bonds and therefore can exist as stereoisomers, e.g., double bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). The present invention encompasses any and all isomers of the compounds described herein, including stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates. Enantiomeric and stereomeric mixtures of compounds and means for separating them into their component enantiomers or stereoisomers are well known. The compounds, salts, or complexes of the invention can be prepared in combination with solvents or water molecules to form solvates and hydrates by routine methods.

[0034] As used herein, the term "coronary artery calcification" refers to the formation of calcific deposits in the coronary arteries. As used herein, the term "effective amount" with respect to (i) a compound of general formula I (e.g., inositol phosphate, inositol phosphate analog, inositol phosphate derivative, or a combination thereof), or (ii) a pharmaceutical composition comprising at least one compound of item (i), is an amount sufficient to produce a beneficial or desired effect. In some embodiments, the beneficial or desired result is, for example, a clinical result, and therefore, "effective amount" depends on the context in which it is applied. In terms of administering an active agent to prevent, inhibit the progression of, or treat cardiovascular calcification, an effective amount of an active agent is, for example, an amount sufficient to (a) inhibit the formation and / or growth of HAP crystals in a specific region of cardiovascular tissue in a subject, (b) slow the progression of the formation and / or growth of HAP crystals in a specific region of cardiovascular tissue in a subject, or (c) reduce, stop, or eliminate symptoms associated with cardiovascular calcification in a subject in need thereof, compared to the same parameters observed in the subject before administration of the active agent or in a control patient population not administered the active agent.

[0035] As used herein, the term "renal failure" refers to a disease that causes a progressive loss of kidney function with a concomitant decrease in glomerular filtration rate (GFR) or index. Renal failure is also known as renal decline or kidney disease. Renal disease can be classified as (i) acute kidney injury (AKI), which is a progressive loss of kidney function that generally causes oliguria and fluid and electrolyte abnormalities, and (ii) chronic kidney disease (CKD), which is a much more gradual loss of kidney function over months or years. Five stages of CKD are defined based on GFR, depending on the degree of renal function: (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 kidney transplantation is necessary to maintain health. AKI and CKD can occur simultaneously, which is known as acute exacerbation of chronic renal failure.

[0036] As used herein, the term "excipient" refers to a substance that aids in the absorption of, stabilizes, activates, or aids in the preparation of a pharmaceutical composition. Thus, examples of excipients used in parenteral formulations include, but are not limited to, antibacterial agents (e.g., benzalkonium chloride, metacresol, thimerosal), co-solvents (e.g., ethanol), buffers, and pH adjusters (e.g., carbonate, citrate, phosphate solutions).

[0037] As used herein, the terms "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and intravenous infusion.

[0038] As used herein, the term "pharmaceutically acceptable vehicle" refers to a substance used in a composition to dilute any of the compounds, excipients, or components contained therein to a determined volume or weight. A pharmaceutically acceptable vehicle is an inactive substance or a substance that has a similar effect to any of the components comprising the pharmaceutical composition of the present invention. The role of the vehicle is to allow the incorporation of other components, to allow better dosing and administration, or to provide consistency and shape to the composition.

[0039] As used herein, the terms "prevent," "preventing," and "prevention" mean inhibiting the onset of or reducing the occurrence of a disease, condition, or symptom associated with cardiovascular calcification in a subject (e.g., preventing the formation or growth of HAP crystals in the coronary arteries, aorta, or aortic valve).

[0040] As used herein, the term "SNF472" refers to a myo-inositol hexaphosphate hexasodium formulation. SNF472 is manufactured by dissolving myo-inositol hexaphosphate hexasodium in saline, followed by pH adjustment and sterile filtration. SNF472 is prepared in three different strengths: (i) 20 mg / mL and (ii) 90 mg / mL in 5 mL single-use vials (pH 5.8-6.2) formulated in saline, and (b) 30 mg / L in 10 mL single-use vials (pH 5.6-6.4) formulated in saline.

[0041] As used herein, the terms "subject," "individual," "animal," or "mammal" refer to any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pets, such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, and cows; primates, such as apes, monkeys, orangutans, and chimpanzees; canines, such as dogs and wolves; felines, such as cats, lions, and tigers; equines, such as horses, donkeys, and zebras; bears, food animals, such as cows, pigs, and sheep; ungulates, such as deer and giraffes; rodents, such as mice, rats, hamsters, and guinea pigs; and the like. In some embodiments, the subject is a human subject. In some embodiments, the subject is a human patient with a disease, condition, or symptom associated with cardiovascular calcification, or at risk of developing said cardiovascular calcification or an associated disease, condition, or symptom. In some further embodiments, the subject is a human patient with a disease, condition, or symptom associated with coronary artery calcification, aortic calcification, or aortic valve calcification, or associated with coronary artery calcification, aortic calcification, or aortic valve calcification, or at risk of developing coronary artery calcification, aortic calcification, or aortic valve calcification, or a disease, condition, or symptom associated with any of them.

[0042] As used herein, the term "substantially" refers to the qualitative condition of exhibiting the complete or nearly complete extent or degree of a desired characteristic or property. Those skilled in the art of biology understand that biological and chemical phenomena rarely, if ever, proceed to completion and / or toward perfection or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0043] As used herein, the term "treating" or "treatment" refers to the administration of a compound or pharmaceutical composition of the present invention to (i) slow progression, (ii) inhibit progression, (iii) halt progression, or (iv) reverse progression of a disease or condition after the appearance of its clinical signs. Controlling disease progression is understood to mean beneficial or desired clinical results, including, but not limited to, alleviation of symptoms, shortening of disease duration, stabilization of the pathological state (particularly to avoid further exacerbations), delay in disease progression, improvement of the pathological state, and remission (partial and complete). Controlling disease progression also includes prolonging survival time compared to the expected survival time if no treatment was applied. Within the context of the present invention, the terms "treat" and "treatment" particularly mean (a) inhibiting further formation and / or growth of HAP crystals in a particular region of cardiovascular tissue in a subject, (b) slowing the progression of HAP crystal formation and / or growth in a particular region of cardiovascular tissue in a subject, or (c) reducing, arresting, or eliminating symptoms associated with cardiovascular calcification in a subject in need thereof.

[0044] compound The compounds for use in the present invention are inositol phosphates, as defined in the first aspect of the present invention, and their analogs and derivatives. As used herein, the term "inositol phosphate" refers to a compound having an inositol ring and 1, 2, 3, 4, 5, or 6 phosphate groups, or a combination thereof. Myo-inositol hexaphosphate (IP6) is an exemplary inositol phosphate of the present invention. In some embodiments, the inositol phosphate is pure (e.g., more than 99% of the inositol phosphate species are the same species, e.g., IP6) or substantially pure (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the inositol phosphate species are the same species, e.g., IP6). In some embodiments, the inositol phosphate is a mixture, e.g., containing varying amounts of IP1, IP2, IP3, IP4, IP5, and IP6. In some embodiments, the inositol phosphates are a racemic mixture.

[0045] The present invention also contemplates inositol phosphate analogs. As used herein, "inositol phosphate analogs" refers to compounds that have rings with different numbers of carbons (i.e., 5 or 7 carbons) relative to the inositol ring, and / or have at least one sulfate or thiophosphate group. For example, compounds that include rings with 5, 6, or 7 carbons and at least one phosphate, sulfate, or thiophosphate group are considered to be inositol phosphate analogs.

[0046] As used herein, the term "inositol phosphate derivative" refers to an inositol phosphate or inositol phosphate analog that contains a heterogeneous moiety (i.e., a group that is not a phosphate, sulfate, or thiophosphate). For example, inositol pentasulfate with a polyethylene glycol heterogeneous moiety or myo-inositol hexaphosphate with a polyglycerin heterogeneous moiety are considered to be inositol phosphate derivatives.

[0047] As used herein, the term "heterologous moiety" refers to a group in a compound of Formula I that is not a phosphate, sulfate, or thiophosphate and that confers desirable properties to such a compound. For example, a heterologous moiety (e.g., polyglycerin or polyethylene glycol) can increase the solubility of a compound. In some embodiments, the heterologous moiety can confer multiple desirable properties (e.g., polyglycerin and polyethylene glycol can increase the solubility and decrease the clearance rate of a compound).

[0048] As used herein, the terms "inositol phosphates of the present invention" and "inositol phosphates of the present invention" are generic terms that encompass "inositol phosphates," "inositol phosphate analogs," "inositol phosphate derivatives," and combinations thereof. In some embodiments, the term "inositol phosphates of the present invention" encompasses pharmaceutical compositions comprising "inositol phosphates," "inositol phosphate analogs," and "inositol phosphate derivatives," or combinations thereof, and pharmaceutically acceptable excipients and carriers. In some embodiments, the term "inositol phosphates of the present invention" encompasses combination formulations that include "inositol phosphates," "inositol phosphate analogs," and "inositol phosphate derivatives," or combinations thereof, and at least one second active agent.

[0049] As used herein, the terms "inositol phosphates of the present invention" and "inositol phosphates of the present invention" are generic terms that encompass "inositol phosphates," "inositol phosphate analogs," "inositol phosphate derivatives," and combinations thereof. In some embodiments, the term "inositol phosphates of the present invention" encompasses compositions comprising "inositol phosphates," "inositol phosphate analogs," and "inositol phosphate derivatives," or combinations thereof, and at least one second active agent.

[0050] Compounds of the present invention that contain a ring with 5, 6, or 7 carbons and at least one sulfate or thiophosphate group, but no phosphate group, would be considered "inositol phosphate analogs" or "inositol phosphate analogs" in the context of the present invention. Thus, the term "inositol phosphates of the present invention" encompasses not only phosphate-containing compounds, but also compounds that contain a ring with 5, 6, or 7 carbons and at least one sulfate or thiophosphate group, but no phosphate group.

[0051] Representative inositol phosphates of the present invention are shown in Figures 1-6. Figure 3 shows numerous examples of inositol phosphates, all of which are in the myo conformation. In addition to myo-inositol, other naturally occurring stereoisomers of inositol are scyllo-, muco-, 1D-chiro-, 1L-chiro-, neo-inositol, allo-, epi-, and cis-inositol. As their names suggest, 1L- and 1D-chiro-inositol are the only pair of inositol enantiomers, but they are enantiomers of each other and not of myo-inositol. It is understood that any exemplary inositol phosphates shown in this disclosure are not limited to the representative conformations shown. Thus, for example, the example shown in Figure 3 would also encompass the corresponding equivalents in the scyllo-, muco-, 1D-chiro-, 1L-chiro-, neo-inositol, allo-, epi-, and cis-inositol conformations. In its most stable conformation, the myo-inositol isomer adopts a chair conformation in which the greatest number of hydroxyls are moved to equatorial positions, which are furthest apart from each other. In this conformation, the naturally occurring myo-inositol has a structure in which five of the six hydroxyls (the first, third, fourth, fifth, and sixth) are equatorial, while the second hydroxyl group is axial.

[0052] [ka]

[0053] Inositol phosphates, analogs and derivatives In some embodiments, R of the compound of general formula I 1、 R 3、 R 5、 R 7、 R9 and R 11 at least one of independently represents H, -X, -OX, -NHX, -NX2, -SX, -OSO3HX, -OSO3X2, or a compound of Formula II, Formula III, or Formula IV, and each X independently represents H, C 1~30 Alkyl, C 2~30 represents alkynyl or Cy1, C 1~30 Alkyl, C 2~30 Alkenyl and C 2~30 Alkynyl can independently be one or more R 14 and Cy1 is optionally substituted with one or more R 15 optionally substituted by; Cy1 represents a 3- to 10-membered carbocyclic or heterocyclic ring, which may be saturated, partially unsaturated or aromatic, said heterocyclic ring having 1 to 4 heteroatoms selected from among O, S and N, said ring may be bonded to the remainder of the molecule via any available C atom, Cy1 is optionally fused to 1 to 4 5- or 6-membered rings, each saturated, partially unsaturated or aromatic, carbocyclic or heterocyclic, said fused heterocyclic rings may contain 1 or 2 heteroatoms selected from among O, N and S; each R 13 are independently H, C 1~30 Alkyl, -NH2, -NHC 1~30 Alkyl or N(C 1~30 alkyl)2, and each C 1~30 The alkyl is optionally substituted independently with one or more halogen, —OH, —CN, and —NO groups; each R 14 and R 15 are independently -OH, C 1~30 Alkoxy, C 1~30 Alkylthionyl, C 1~30 Acyloxy, phosphate, halogen, trihalo C 1~30 Represents alkyl, nitrile azide.

[0054] In some implied embodiments, each X is independently selected from H, C 1~30 represents alkyl or Cy1, C 1~30 Alkyl is one or more R 14 and Cy1 is optionally substituted by one or more R 15 and optionally substituted by each R 14 and R 15 are independently -OH, C 1~30 Alkoxy, C 1~30 Alkylthionyl, C 1~30 Acyloxy, phosphate, halogen, trihalo C 1-30 In some embodiments, each X represents H, C, alkyl, nitrile, or azide. 1~30 In some embodiments, each X represents H.

[0055] In some additional embodiments, R1, R3, R5, R7, R9 and R 11 At least one of the groups independently represents a compound of Formula II, Formula III, or Formula IV, and each R 13 are independently H, C 1~30 Alkyl, -NH2, -NHC 1~30 Alkyl or -N(C 1~30 alkyl)2, and each C 1~30 The alkyl is optionally substituted independently with one or more halogen, —OH, —CN, and —NO groups; R, R, R, R, R 10 and R 12 independently represents H.

[0056] In a further embodiment, R1, R3, R5, R7, R9 and R 11 independently represent a compound of Formula II, Formula III, or Formula IV, and each R 13 are independently H or C 1~30 represents alkyl, and each C 1~30 The alkyl is optionally substituted independently with one or more halogen, —OH, —CN, and —NO groups; R, R, R, R, R 10 and R 12 independently represents H.

[0057] In additional embodiments, R1, R3, R5, R7, R9 and R 11 at least one of R represents a compound of Formula II, Formula III, or Formula IV; 13 are independently H or C 1~30 In another embodiment, R1, R3, R5, R7, R9 and R 11 at least one of R represents a compound of Formula II, Formula III or Formula IV; 13 represents H.

[0058] In detailed embodiments, the compound is inositol hexaphosphate (IP6). In other embodiments, the compound is inositol monophosphate (IP1), inositol diphosphate (IP2), inositol triphosphate (IP3), inositol tetraphosphate (IP4), or inositol pentaphosphate (IP5). In some embodiments, the compound comprises a combination of IP1, IP2, IP3, IP4, IP5, and / or IP6. In some embodiments, IP6 can form other inositol phosphates (IP5, IP4, IP3, IP2, IP1) by dephosphorylation in vivo. Inositol is considered to mean any isomeric form of the molecule, e.g., myo-inositol.

[0059] In some embodiments, compounds for use in the present invention have Formula I, wherein: R7 is OSO3 - and R9, R5, R3, R1 and R 11 is OPO3 2- , OPSO2 2- or OSO3 - are independently selected from; R9, R5 and R1 are OPO3 2- and R7, R3 and R 11 is OSO3 - and; R9, R5 and R1 are OSO3 - and R7, R3 and R 11 is OPO32- and; R3, R1 and R 11 is OSO3 - and R9, R7 and R5 are OPO3 2- and; R3, R1 and R 11 is OPO3 2- and R9, R7 and R5 are - and; R7 and R1 are OPO3 2- and R9, R5, R3, and R 11 is OPO3 2- and; R7 and R1 are - and R9, R5, R3, and R 11 is OPO3 2- and; R7 and R5 are OPO3 2- and R9, R3, R1, and R 11 is OSO3 - or R7 and R5 are OSO3 - and R9, R3, R1, and R 11 is OPO3 2- is one of the following.

[0060] The inositol phosphates of the present invention also include compounds produced as metabolites during physiological dephosphorylation (or desulfation or dethiosulfation, in the case of compounds containing sulfate or thiophosphate groups).

[0061] In some embodiments, the compounds administered in the doses according to the methods disclosed herein are prodrugs that, after hydrolysis or other intracellular or extracellular processing, generate the inositol phosphates of the invention.

[0062] The inositol phosphates of the present invention also include any combination of the inositol phosphates, inositol phosphate analogs, and derivatives thereof disclosed herein. All compounds of Formula I contain a group with a COP or COS bond, which confers affinity to calcium-containing crystals and a bond that is sufficiently labile to be hydrolyzed in vivo, thereby preventing irreversible binding to calcium-containing crystals, such as hydroxyapatite (HAP) in bone. If such irreversible binding were to occur, it would have a negative effect on bone remodeling, as do bisphosphonates when administered long-term because they contain PCP bonds that cannot be hydrolyzed by the body. In the other extreme case of phosphorylated compounds that do not contain the COP bond, such as pyrophosphate, the POP bond means that they are too easily hydrolyzed in the intestinal tract, meaning that only parenteral administration is feasible. Compounds of the present invention that contain COP bonds, COS bonds, and combinations thereof represent a good middle ground due to their efficacy and the fact that the body has mechanisms for excreting the compounds, thereby reducing the risk of side effects (e.g., compounds with PCP bonds can exhibit half-lives of several months in vivo, thereby affecting, for example, bone remodeling).

[0063] The term "alkyl" or "alkyl group" in the context of the present invention means a saturated hydrocarbon moiety, which may be straight-chain, branched-chain, cyclic, or cyclic with linear or branched side chains. The term alkyl includes partially unsaturated hydrocarbons, such as propenyl. Examples are methyl, ethyl, n- or isobutyl, n- or cyclohexyl. The term alkyl can be extended to alkyl groups linked or bridged by heteroatoms. Heteroatoms in the context of the present invention are nitrogen (N), sulfur (S), and oxygen (O).

[0064] An "amine functional group" or "amine group" is an NR'R" functional group, where R' and R" are independently selected from hydrogen and C1-C5 alkyl. In some embodiments, R' and R" are selected from hydrogen and C1-C3 alkyl. A "hydroxy functional group" or "hydroxy group" is OH.

[0065] A "thiol functional group" or "thiol group" is SH. A "carboxylic acid functional group" or "carboxylic acid group" is COOH or its anion, COO - "Carboxylic acid amide" is CONR'R'', where R' and R'' independently have the meanings given above. "Sulfonic acid" is SO3H. "Sulfonic acid amide" is SO2NR'R'', where R' and R'' independently have the meanings given above.

[0066] "C1-C3 alkyl" in the context of the present invention means a saturated, straight-chain or branched hydrocarbon having 1, 2, or 3 carbon atoms, in which one carbon-carbon bond may be unsaturated and one CH2 moiety may be replaced with oxygen (ether bridge). Non-limiting examples of C1-C3 alkyl are methyl, ethyl, propyl, prop-2-enyl, and prop-2-ynyl.

[0067] "C1-C5 alkyl" in the context of the present invention means a saturated, linear or branched hydrocarbon having 1, 2, 3, 4 or 5 carbon atoms, in which one or two carbon-carbon bonds may be unsaturated and one CH2 moiety may be replaced with oxygen (ether bridge). Non-limiting examples for C1-C5 alkyl include the examples given above for C1-C3 alkyl, as well as 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. "C3-C 10"Alkyl" means a saturated, straight-chain or branched hydrocarbon having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, in which 1, 2, or 3 carbon-carbon bonds may be unsaturated and one CH2 moiety may be replaced with oxygen (ether bridge).

[0068] The term "C" as a group or part of a group 1~30 "Alkyl" means a straight or branched chain alkyl group containing from 1 to 30 carbon atoms, including, among others, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, decyl, and dodecyl groups.

[0069] The term “C 2~30 "Alkenyl" means a straight or branched alkyl chain containing 2 to 30 carbon atoms, also containing one or more double bonds. Examples include ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, and 1,3-butadienyl, among others.

[0070] The term “C 2~30 "Alkynyl" means a straight or branched alkyl chain containing 2 to 30 carbon atoms and also containing one or more triple bonds. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1,3-butadiynyl, among others.

[0071] The term "Cy1 group" refers to a 3- to 10-membered carbocyclic or heterocyclic ring, which may be saturated, partially unsaturated, or aromatic, and is bonded to the rest of the molecule by any available C atom. When it is a heterocyclic ring, Cy1 contains 1 to 4 heteroatoms selected from among N, O, and S. Furthermore, Cy1 can be optionally fused with a 4-, 5-, or up to 6-membered carbocyclic or heterocyclic ring, which may be saturated, partially unsaturated, or aromatic. When the fused ring is a heterocyclic ring, the ring contains 1 or 2 heteroatoms selected from among N, O, and S. Examples of Cy1 include, among others, 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.

[0072] "C" as a group or part of a group 1~30 "Alkoxy group" means -OC 1~30 means an alkyl group, C 1~30 The alkyl moiety has the same meaning as above. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0073] "C" as a group or part of a group 1~30 The "alkylthionyl group" is -SOC 1~30 means an alkyl group, C 1~30 The alkyl moiety has the same meaning as above. Examples include methylthionyl, ethylthionyl, propylthionyl, isopropylthionyl, butylthionyl, isobutylthionyl, sec-butylthionyl and tert-butylthionyl.

[0074] "C" as a group or part of a group 1~30 "Acyloxy group" means -COC 1~30 means an alkyl group, C 1~30 The alkyl moiety has the same meaning as above. Examples include acetyl, ethanoyl, propanoyl and 2,2-diisopropylpentanoyl.

[0075] The term "halogen" or its abbreviation halo refers to fluorine, chlorine, bromine and iodine. "Trihalo C 1~30 "Alkyl group" means a C alkyl group as defined above, with three halogen groups. 1~30 means the group resulting from the replacement of three hydrogen atoms of an alkyl group. Examples include trifluoromethyl, tribromomethyl, trichloromethyl, triiodomethyl, trifluoroethyl, tribromoethyl, trichloroethyl, triiodoethyl, tribromopropyl, trichloropropyl, and triiodopropyl, among others.

[0076] -NHC 1~30 "Alkyl group" is defined as above. 1~30 means the group resulting from the replacement of one hydrogen atom of an -NH group by an alkyl group. Examples include methylamine, ethylamine, propylamine, butylamine, and pentylamine, among others.

[0077] "-N(C 1~30 "Alkyl group" is defined as above. 1~30 means the group resulting from the replacement of the two hydrogen atoms of an -NH group by an alkyl group. Examples include dimethylamine, diethylamine, diisopropylamine, dibutylamine, and diisobutylamine, among others.

[0078] The phrase "optionally substituted with one or more" refers to the possibility that a group can be substituted with one or more (e.g., 1, 2, 3, or 4) substituents. In some embodiments, if the group has enough available positions for substitution, the group can be substituted with 1, 2, or 3 substituents, or even 1 or 2 substituents. If present, the substituents can be the same or different and can be at any available position.

[0079] In some embodiments, inositol phosphates of the present invention include compounds disclosed in WO2017098033 and WO2017098047, and US 9358243. In some embodiments, the inositol phosphates of the present invention used include compounds disclosed in Figures 1-6.

[0080] In some embodiments, the inositol phosphates, inositol phosphate analogs, and derivatives thereof are represented by Formula (VIII), Formula (IX), or Formula (X):

[0081] [ka]

[0082] This includes compounds of the formula: wherein each X independently represents OPO3 2- , OPSO2 2- , or OSO3 - Z is an alkyl chain containing 1 to 3 carbon and / or heteroatoms, and optionally containing an X group, and X is also OPO3 2- , OPSO2 2- , or OSO3 - Also selected from R 1 is an optional heterologous moiety (see Section 2.2. below). In some embodiments, a molecule comprises two or more heterologous moieties, in which case the heterologous moieties may be the same or different.

[0083] In some embodiments, Z, as used in formula (VIII), is CH, CHX, CHR 1 , CXR 1 , CH2-CH2, CH2-CHX, CHX-CHX, CHR 1 -CHX, CXR 1 -CHX, CHR 1 -CH2, CXR 1 -CH2, CHR 1 -CHOH, CH2-CH2-CH2, CH2-O-CH2, CHOH-CH2-CH2, CHOH-CHOH-CHR 1 , CHOH-CHR 1 -CHOH, CHX-CH2-CH2, CH2-CHX-CH2, CHX-CHX-CH2, CHX-CH2-CHX or CHX-CHR 1 -CHX, where X is independently OPO3 2- , OPSO2 2- , and OSO3 - is selected from.

[0084] In some embodiments, Z, as used in formula (VIII), is (CHX) p CHX(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 heterologous moieties (e.g., PEG), and the remaining X's may be OPO3 2- , OPSO2 2- , and OSO3 - In some embodiments, all X in Z are independently selected from OPO3 2- In some embodiments, not all Xs in Z are OSO3 - This is not necessarily the case.

[0085] In some embodiments, one, two, or three of the X's in the compound of Formula (VIII), Formula (IX), or Formula (X) can be heterologous moieties, and the remaining X's are OPO3 2- , OPSO2 2- , or OSO3 - can be independently selected from

[0086] The above formula (VII) describes a 5-, 6-, or 7-membered alkyl ring, with one or more optional hetero moieties attached to one of the carbon atoms forming the ring.

[0087] In some embodiments, for example, the inositol phosphates, inositol phosphate analogs, and derivatives thereof used in the methods and compositions disclosed herein include compounds of formula (XI) or formula (XII).

[0088] [ka]

[0089] [In the formula, X 2 is OSO3 - and X 1 , X 3 , X 4 , X 5 and X 6 is OPO3 2- , OPSO2 2- or OSO3 - are independently selected from; X 1 , X 3 and X 5 is OPO3 2- and X 2 , X 4 and X 6 is OSO3 - and; X 1 , X 3 and X 5 is OSO3 - and X 2 , X 4 and X 6 is OPO3 2- and; X 4 , X 5 and X 6 is OSO3 - and X 1 , X 2 and X 3 is OPO32- and; X 4 , X 5 and X 6 is OPO3 2- and X 1 , X 2 and X 3 is OSO3 - and; X 2 and X 5 is OPO3 2- and X 1 , X 3 , X 4 , and X 6 is OPO3 2- and; X 2 and X 5 is OSO3 - and X 1 , X 3 , X 4 , and X 6 is OPO3 2- and; X 2 and X 3 is OPO3 2- and X 1 , X 4 , X 5 , and X 6 is OSO3 - or X 2 and X 3 is OSO3 - and X 1 , X 4 , X 5 , and X 6 is OPO3 2- is].

[0090] In some embodiments, the inositol phosphates or their metabolites of the present invention can be detected and / or quantified using the methods disclosed in US 9612250. See also US 8377909, US 8778912, and US 20070066574.

[0091] The compounds disclosed herein can be in any form commonly used in pharmaceutical technology.Detailed embodiments include, but are not limited to, sodium salt, magnesium salt, potassium salt, ammonium salt, free acid, or a mixture thereof.Other pharmaceutically acceptable salts are known to those skilled in the art and can be easily obtained.In a detailed embodiment, the compound for use as defined in the first aspect of the present invention is a sodium salt, for example, inositol hexaphosphate hexa-sodium salt.

[0092] The present invention also contemplates the sodium salts of inositol monophosphate, inositol diphosphate, inositol triphosphate, inositol tetraphosphate, and inositol pentaphosphate in any of the isomeric forms of inositol, particularly myo-inositol. A particular example of a compound for use in the present invention is myo-inositol hexaphosphate hexasodium salt.

[0093] dissimilar parts In some embodiments, the present invention relates to compounds of general formula I as defined above, wherein the heterologous moiety is a group of formula V, a group of formula VI and a group of formula VII:

[0094] [ka]

[0095] is selected from n is an integer ranging from 2 to 200, and R 13 is selected from H, methyl or ethyl.

[0096] In some embodiments, compounds for use in the present invention, such as inositol phosphate derivatives of the present invention, can contain one or more groups selected from groups of formulae V, VI, and VII. These groups are heterologous moieties that confer advantageous properties relative to a corresponding molecule lacking such one or more heterologous moieties. Examples of such advantageous properties that can be conferred to an inositol phosphate or inositol phosphate analog by a heterologous moiety or combination thereof include, but are not limited to, (a) increased solubility, (b) reduced degradation or metabolic rate, (c) increased plasma half-life, (d) reduced hepatic metabolic rate, (e) reduced clearance rate, (f) reduced toxicity, (g) reduced irritability, and (h) reduced side effects, among others. These advantageous properties can be assessed or quantified without undue experimentation using methods known in the art.

[0097] In some embodiments, the heterologous moiety is, for example, polyethylene glycol (PEG) or polyglycerin (PG). Thus, in some embodiments, the compound for use in the present invention is any of the compounds defined in the above-disclosed embodiments that includes a heterologous moiety, i.e., one of the groups of formula I is selected from the groups of formulas V, VI, and VII. In some embodiments, the heterologous moiety includes polyethylene glycol (PEG). In some embodiments, the heterologous moiety consists of polyethylene glycol, i.e., R1, R3, R5, R7, R9, and R of the compound of formula I according to the first aspect of the present invention. 11 is a group of formula V. Alternatively, the heterologous moiety comprises a polyglycerol. In some embodiments, the heterologous moiety is composed of a polyglycerol, i.e., R, R, R, R and R of the compound of formula I according to the first aspect of the present invention. 11At least one of the residues is selected from the group of formula VI or VII. In other embodiments, the compound of formula I according to the first aspect of the invention contains one, two, or three groups selected from the group of formula VI or VII, e.g., two PEGs (groups of formula V), three PEGs, three polyglycerols (groups of formula VI), three PGs, or any combination thereof, e.g., one PEG and one PG, or two PEGs and one polyglycerol. In some embodiments, all of the residues of formula I (i.e., those not selected from groups V, VI, and VII) are groups selected from II, III, and IV. In some embodiments, the compound of formula I according to the first aspect of the invention contains two groups selected from the group of formula VI or VII, e.g., two PEGs (groups of formula V) or three polyglycerols (groups of formula VI), or one PEG and one polyglycerol, and the residues are all groups of formula II. In some embodiments, R3 and R7 of the compound of formula I are selected from groups of formula V, VI, and VII. In some embodiments, R3 and R7 of the compound of formula I are groups of formula V, and R1, R5, R9, and R of the compound of formula I are groups of formula V. 11 is a group of formula II.

[0098] Groups of formulas V, VI and VII are R 13 =H, methyl, or ethyl, and n is an integer from 2 to 200. In some embodiments, R 13In a detailed embodiment, 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, 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, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 209, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021 58, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 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, or 200.

[0099] In some embodiments, n is 2 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100, 100 to 110, 110 to 120, 120 to 130, 130 to 140, 140 to 150, 150 to 160, 160 to 170, 170 to 180, 180 to 190, or 190 to 200.

[0100] In some specific embodiments, n has a value of 2-200, 2-20, 10-30, or 9-45. In some embodiments, the PEG is a branched PEG, which has 3 to 10 PEG chains emanating from a central core group.

[0101] In some embodiments, the PEG moiety is a monodisperse polyethylene glycol. In the context of the present invention, a monodisperse polyethylene glycol (mdPEG) is a PEG having a single, defined chain length and molecular weight. mdPEG is typically produced by separation from a polymerization mixture by chromatography. In some formulas, the monodisperse PEG moiety is given the abbreviation mdPEG. In some embodiments, the PEG is a star PEG. Star PEGs have 10 to 100 PEG chains emanating from a central core group.

[0102] In some embodiments, the PEG is a Comb PEG, which has multiple PEG chains typically grafted onto a polymer backbone. In some embodiments, the PEG has a molar mass of 100 g / mol to 3000 g / mol, particularly 100 g / mol to 2500 g / mol, and more particularly approximately 100 g / mol to 2000 g / mol. In some embodiments, the PEG has a molar mass of 200 g / mol to 3000 g / mol, particularly 300 g / mol to 2500 g / mol, and more particularly approximately 400 g / mol to 2000 g / mol.

[0103] In some embodiments, the PEG is 100 , PEG 200 , PEG 300 , PEG 400 , PEG 500 , PEG 600 , PEG 700 , PEG 800 , PEG 900 , PEG 1000 , PEG 1100 , PEG 1200 , PEG 1300 , PEG 1400 , PEG 1500 , PEG 1600 , PEG 1700 , PEG1800 , PEG 1900 , PEG 2000 , PEG 2100 , PEG 2200 , PEG 2300 , PEG 2400 , PEG 2500 , PEG 1600 , PEG 1700 , PEG 1800 , PEG 1900 , PEG 2000 , PEG 2100 , PEG 2200 , PEG 2300 , PEG 2400 , PEG 2500 , PEG 2600 , PEG 2700 , PEG 2800 , PEG 2900 , or PEG 3000 In one particular aspect, the PEG is 400 In another particular embodiment, the PEG is 2000 is.

[0104] In some embodiments, the inositol phosphates of the present invention are mdPEG inositol phosphate derivatives modified at positions 4 and 6. In some embodiments, the inositol phosphates of the present invention are inositol-1,2,3,5-tetraphosphate-4,6-bisPEG 200 , inositol-1,2,3,5-tetraphosphate-4,6-bisPEG 300 , inositol-1,2,3,5-tetraphosphate-4,6-bisPEG 400 , inositol-1,2,3,5-tetraphosphate-4,6-bisPEG 500 , inositol-1,2,3,5-tetraphosphate-4,6-bisPEG 600 , inositol-1,2,3,5-tetraphosphate-4,6-bisPEG 700 , inositol-1,2,3,5-tetraphosphate-4,6-bisPEG 800 , inositol-1,2,3,5-tetraphosphate-4,6-bisPEG 900 , or inositol-1,2,3,5-tetraphosphate-4,6-bisPEG 1000In some embodiments, the inositol phosphate of the present invention is inositol-1,2,3,5-tetraphosphate-4,6-bisPEG. 100 is.

[0105] In other particular embodiments, R3 and / or R7 of the compound of formula I are groups of formula V, R 13 is H and n is an integer from 9 to 45. In other detailed embodiments, R3 and R7 of the compound of formula I are groups of formula V, and R 13 is H, n is an integer from 9 to 45, and R1, R5, R9 and R 11 are all groups of formula II. In other particular embodiments, compounds of formula I have R3 and R7 = groups of formula V, where R 13 is H, n is an integer from 9 to 45, and R1, R5, R9 and R 11 are all groups of formula II.

[0106] In some other embodiments, the heterologous moiety has 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 embodiments, n has a value from 3 to 20. In some embodiments, n has a value from 10 to 30. In some alternatives of these embodiments, n has a value from 9 to 45. In some embodiments, the heterologous moiety is a polyglycerol (PG) described by the formula (R 3 -O-(CH2-CHOR 5 -CH2-O) n -) [where R 5 is hydrogen] or a branched polyglycerol described by the formula (R 3 -O-(CH2-CHOH-CH2-O) n -) [where R 3 is hydrogen, methyl, or ethyl. In some embodiments, the heterologous moiety is a straight chain glycerol described by the formula (R 3 -O-(CH2-CHOR 5 -CH2-O) n -) [where R 5is hydrogen] or a hyperbranched polyglycerol described by the formula (R 3 -O-(CH2-CHOR 6 -CH2-O) n -) [where R 6 is hydrogen] or a glycerol chain described by the formula (R 3 -O-(CH2-CHOR 7 -CH2-O) n -) [where R 7 is hydrogen] or a glycerol chain described by the formula (R 3 -O-(CH2-CHOH-CH2-O) n -) [where R 3 is hydrogen, methyl or ethyl. Hyperbranched glycerols and methods for their 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.

[0107] In some embodiments, PG has a molar mass of 100 g / mol to 3000 g / mol, particularly 100 g / mol to 2500 g / mol, and more particularly approximately 100 g / mol to 2000 g / mol.In some embodiments, PG has a molar mass of 200 g / mol to 3000 g / mol, particularly 300 g / mol to 2500 g / mol, and more particularly approximately 400 g / mol to 2000 g / mol.

[0108] In some embodiments, PG is 100 , P.G. 200 , P.G. 300 , P.G. 400 , P.G. 500 , P.G. 600 , P.G. 700 , P.G. 800 , P.G. 900 , P.G. 1000 , P.G. 1100 , P.G. 1200 , P.G. 1300 , P.G. 1400 , P.G.1500 , P.G. 1600 , P.G. 1700 , P.G. 1800 , P.G. 1900 , P.G. 2000 , P.G. 2100 , P.G. 2200 , P.G. 2300 , P.G. 2400 , P.G. 2500 , P.G. 1600 , P.G. 1700 , P.G. 1800 , P.G. 1900 , P.G. 2000 , P.G. 2100 , P.G. 2200 , P.G. 2300 , P.G. 2400 , P.G. 2500 , P.G. 2600 , P.G. 2700 , P.G. 2800 , P.G. 2900 , or PG 3000 In one particular embodiment, the PG is PG 400 In another detailed embodiment, the PG is PG 2000 is.

[0109] In other particular embodiments, R3 and / or R7 of the compound of formula I are groups of formula VI, R 13 is H and n is an integer from 9 to 45. In other detailed embodiments, R3 and R7 of the compound of formula I are groups of formula VI, and R 13 is H, n is an integer from 9 to 45, and R1, R5, R9 and R 11 are all groups of formula II. In other particular embodiments, compounds of formula I have R3 and R7 = groups of formula VI, where R 13 is H, n is an integer from 9 to 45, and R1, R5, R9 and R 11 are all groups of formula II.

[0110] Pharmaceutical compositions and combination formulations In another aspect, the present invention also relates to pharmaceutical compositions comprising a compound defined in any of the above-disclosed aspects. In some aspects, the pharmaceutical compositions comprise a compound defined in any of the above-disclosed aspects, together with one or more pharmaceutically acceptable excipients or carriers. In some aspects, these pharmaceutical compositions are for use in treating, inhibiting the progression of, or preventing (a) cardiovascular calcification, or (b) a subject in need of treating, inhibiting the progression of, or preventing a disease, condition, or symptom associated with cardiovascular calcification, or (c) at risk of developing said cardiovascular calcification, related disease, condition, or symptom. In some further embodiments, the pharmaceutical composition of the present invention is for use in treating, inhibiting the progression of, or preventing (a) coronary artery calcification, aortic calcification, or aortic valve calcification, or (b) a disease, condition, or symptom associated with coronary artery calcification, aortic calcification, or aortic valve calcification, or in a subject in need of such treatment, inhibiting the progression of, or preventing such treatment, or (c) a subject at risk of developing coronary artery calcification, aortic calcification, or aortic valve calcification, or a disease, condition, or symptom associated with any of them. In some further embodiments, the pharmaceutical composition of the present invention constitutes a combined preparation containing at least one second active agent.

[0111] The pharmaceutical composition can comprise from about 1% to about 95% of the compound defined in any of the above-disclosed embodiments. In some embodiments, the pharmaceutical composition of the present invention can comprise, for example, from about 20% to about 90%, or 20% to 80%, or 20% to 70%, or 20% to 60%, or 20% to 50%, or 30% to 90%, or 40% to 90%, or 50% to 90%, or 60% to 90%, or 30% to 70% of the compound defined in any of the above-disclosed embodiments.

[0112] In some embodiments, the concentration of an inositol phosphate of the invention (e.g., myo-inositol hexaphosphate, or an analog or derivative thereof, or a combination thereof) in each dose of the pharmaceutical composition is about 12.5 mM to about 135 mM. In some versions of this embodiment, the concentration of an inositol phosphate of the invention (e.g., myo-inositol hexaphosphate, or an analog or derivative thereof, or a combination thereof) in each dose of the pharmaceutical composition is about 25 mM, about 39 mM, or about 114 mM.

[0113] Pharmaceutical composition formulations suitable for parenteral administration include a compound defined in any of the above-disclosed embodiments mixed with a pharmaceutically acceptable carrier (such as, for example, sterile water or sterile isotonic saline). Such formulations can be prepared, packaged, or sold in a form suitable for rapid or continuous administration. Injectable formulations can be prepared, packaged, or sold in unit dosage form, for example, in ampoules or in multi-dose containers containing a preservative. Formulations for parenteral administration 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 further comprise one or more additional ingredients, including, but not limited to, suspending agents, stabilizing agents, or dispersing agents.

[0114] In some embodiments, in formulations for parenteral administration, the active agent (e.g., a compound defined in any of the embodiments disclosed above) is provided in a dry (i.e., powder or granules) form for reconstitution with a suitable vehicle (e.g., sterile, pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0115] The pharmaceutical compositions can be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution can be formulated according to known techniques and can contain, in addition to the active agent (e.g., a compound defined in any of the above-disclosed embodiments), additional ingredients such as dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations can be prepared using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils, such as synthetic mono- or di-glycerides.

[0116] Other parenterally administrable formulations that are useful include those that contain the active agent (e.g., a compound defined in any of the above-disclosed embodiments) in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system.

[0117] Compositions for sustained release or implantation may include pharmaceutically acceptable polymeric or hydrophobic materials, such as emulsions, ion exchange resins, sparingly soluble polymers, or sparingly soluble salts.

[0118] The controlled release or sustained release formulation of the pharmaceutical composition of the present invention can be prepared using conventional technology.In some cases, the dosage form to be used can be provided as a slow release or controlled release of one or more active agents therein, for example, by using hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres, or combinations thereof, to provide a desired release profile in various proportions.Suitable controlled-release formulations known in the art, including those described herein, can be easily selected for use with the pharmaceutical composition of the present invention.Therefore, single unit dosage forms adapted for controlled release, suitable for parenteral or topical administration, such as injectable solutions, gels, creams, and ointments, are encompassed by the present invention.

[0119] Most controlled-release pharmaceutical products have a common goal of improving therapy compared to that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release formulation in medical treatment will feature the use of a minimum amount of active agent to cure or manage a condition in a minimum period of time. Advantages of controlled-release formulations include extended activity of the active agent, reduced dosing frequency, and improved patient compliance. Furthermore, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the active agent, and therefore may affect the occurrence of side effects.

[0120] Most controlled-release formulations are designed to initially release one amount of active agent to rapidly produce the desired therapeutic effect, and then gradually and continuously release another amount of active agent to maintain this level of therapeutic effect over an extended period of time. In order to maintain this steady level of active agent in the body, the active agent must be released from the dosage form at a rate that will replace the amount of active agent being metabolized or excreted from the body.

[0121] 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 one or more compounds, including but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres, or combinations thereof, that facilitate the controlled-release of an active agent.

[0122] In some embodiments, the formulations of the present invention can be, but are not limited to, short-term, fast-release, and controlled-release, including sustained-release, delayed-release, and pulsatile-release formulations. The term sustained release is used in its conventional sense to refer to an active agent formulation (e.g., a compound defined in any of the above-disclosed embodiments) that provides for gradual release of an active agent in therapy over an extended period of time, and that can, but is not necessarily, result in substantially constant blood levels of the active agent over an extended period of time, which can be as long as one month or more, and should be a longer release than if the same amount of agent were administered in the form of a bolus dose.

[0123] For sustained release, the compound can be formulated with a suitable polymer or hydrophobic material that provides the compound with sustained release properties.Thus, the compound for use in the method of the present invention can be administered in the form of microparticles, for example, in the form of wafers or disks by injection or implantation.In some embodiments, the compound of the present invention is administered to a patient alone or in combination with another pharmaceutical agent using a sustained release formulation.

[0124] The term delayed release is used herein in its conventional sense to refer to an active agent formulation that provides for initial release of the active agent after some delay following administration of the active agent. The delay can be from about 10 minutes to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to an active agent formulation that releases the active agent in a manner that results in a pulsed plasma profile of the active agent after administration. The term immediate release is used herein in its conventional sense to refer to an active agent formulation that provides for release of the active agent immediately after administration.

[0125] In the context of the present invention, the term "non-bolus sustained release form" means that administration of an active agent to a subject lasts for at least 1 minute in the case of parenteral injection, e.g., intravenous or subcutaneous injection, and for at least 30 minutes in the case of parenteral infusion, e.g., intravenous infusion administration.

[0126] Additional formulations and dosage forms of the compositions of the present invention include those disclosed in US6340475, US6488962, US6451808, US5972389, US5582837, and US5007790; US20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820; WO2003035041, WO200303504 0, WO2003035029, WO200335177, WO2003035039, WO2002096404, WO2002032416, WO2001097783, WO2001056544, WO2001032217, WO1998055107, WO1998011879, WO1997047285, WO1993018755, and WO1990011757.

[0127] The pharmaceutical preparations according to the invention are prepared by methods known in the art, in particular by conventional mixing, coating, granulating, dissolving or lyophilizing processes. The present invention also provides a compound, a combination of compounds, or a pharmaceutical formulation as defined in any of the above aspects of the invention, given in its broadest definition or as specified in any of the aspects set out above for use as a pharmaceutical.

[0128] Further aspects of the present invention relate to combination preparations 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 administered periodically to subjects with renal failure. In some embodiments, the combination preparations are administered to subjects undergoing dialysis. Some of these second active agents alter the thermodynamics of the HAP crystallization process by regulating the concentration of ions present in the structure of calcium-containing crystals that directly or indirectly cause renal failure-related diseases.

[0129] Thus, in some embodiments, the second active agent is selected from the group consisting of vitamins, calcimimetics, bisphosphonates, phosphate binders, thiosulfates, pyrophosphates, citrates, diuretics, antihypertensives, cholesterol-lowering agents, phosphodiesterase inhibitors, and combinations thereof.

[0130] In some embodiments, the vitamin in the combination formulation is vitamin B, vitamin D, vitamin K, or a combination thereof. In some embodiments, the calcimimetics in the combination formulation are cinacalcet ((R)-N-[1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine, KAI-4169 (etelcalcetide), NPS R-467 (((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 embodiments, the bisphosphonate in the combination formulation may be nitrogen-containing or nitrogen-free. In some further embodiments, the bisphosphonate is alendronate, clodronate, etidronate, ibandronate, monidronate, neridronate, olpadronate, pamidronate, parnidronate, risedronate, tiludronate, zoledronate, or a combination thereof.

[0131] In some embodiments, the phosphate binder in the combination formulation 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 further embodiments, the phosphodiesterase inhibitor in the combination formulation is cilostazol, pentoxifylline, or a combination thereof.

[0132] In some embodiments, the diuretic in the combination formulation is a thiazide, a thiazide-like (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 further embodiments, the thiazide is chlorothiazide, epithiazide, bendroflumethiazide, hydrochlorothiazide, or a combination thereof.

[0133] In some embodiments, the antihypertensive agent in the combination formulation is a diuretic, an adrenergic blocker (e.g., a beta-blocker, an alpha-blocker, a mixed combination thereof), a calcium channel blocker (e.g., a 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 further embodiments, the cholesterol-lowering agent in the combination formulation is a statin, a fibrate, niacin, a bile acid sequestrant, ezetimibe, lomitapide, a phytosterol, orlistat, or a combination thereof.

[0134] In some embodiments, (a) the compound and / or (b) the pharmaceutical composition according to the present invention and (c) the at least one second active agent of the combined formulation are administered separately, simultaneously, or sequentially to a subject in need thereof. In some further embodiments, (a) the compound and / or (b) the pharmaceutical composition according to the present invention and (c) the at least one second active agent of the combined formulation are mixed prior to their administration to a subject in need thereof.

[0135] Methods and Routes of Administration In some embodiments, the compound, pharmaceutical composition or combined preparation is provided in an effective amount as defined in any of the above embodiments.The compound, pharmaceutical composition or combined preparation can be administered parenterally, for example, intravenously, intraperitoneally, intramuscularly, intraarterially, intradermally, intrathecally, epidurally, or spinally or subcutaneously.Parenteral administration can be by bolus injection or intravenous infusion.

[0136] In a detailed embodiment of the invention, myo-inositol hexaphosphate (or a formulation comprising myo-inositol hexaphosphate, such as SNF472) is administered by intravenous infusion. In another detailed embodiment of the invention, myo-inositol hexaphosphate is administered subcutaneously. In another embodiment, a derivative of inositol or a myo-inositol hexaphosphate derivative, such as a compound in which R3 and R7 = a group of formula V, where R 13 is H, n is an integer from 2 to 200, and R1, R5, R9 and R 11 is any group of formula II (or a sodium salt thereof), is administered by intravenous infusion. In another embodiment, a compound of formula I having a derivative of inositol or a myo-inositol hexaphosphate derivative, e.g., R3 and R7 = a group of formula V, where R 13 is H, n is an integer from 2 to 200, and R1, R5, R9 and R 11 is all groups of formula II (or sodium salts thereof) is administered subcutaneously.

[0137] In some embodiments, the dose of inositol phosphates of the present invention comprises about 200 mg to about 700 mg of inositol phosphate, inositol phosphate analog, inositol phosphate derivative, or combination thereof per administration. In some embodiments, when the disease or condition being treated or prevented is related to coronary artery calcification, aortic calcification, or aortic valve calcification in a subject with renal failure (e.g., a stage 5 CKD patient), the dose is about 300 mg to 600 mg of inositol phosphates of the present invention per administration.

[0138] In some embodiments, the dose of an inositol phosphate of the present invention (e.g., myo-inositol hexaphosphate) is about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, or about 600 mg to about 700 mg per administration.

[0139] In some embodiments, the dose of an inositol phosphate of the present invention (e.g., myo-inositol hexaphosphate) is about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 300 mg to about 350 mg, about 350 mg to about 400 mg, about 400 mg to about 450 mg, about 450 mg to about 500 mg, about 500 mg to about 550 mg, about 550 mg to about 600 mg, or about 650 mg to about 700 mg per administration.

[0140] In some embodiments, the dose of an inositol phosphate of the invention (e.g., myo-inositol hexaphosphate) is about 200 mg to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 700 mg, about 200 mg to about 500 mg, about 300 mg to about 600 mg, or 400 mg to about 700 mg per administration.

[0141] In some embodiments, the dose of an inositol phosphate (e.g., myo-inositol hexaphosphate) of the present invention is about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, 20 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, or about 700 mg.

[0142] In some embodiments, the dose of the inositol phosphates of the present invention (e.g., myo-inositol hexaphosphate) is about 210 mg to about 700 mg, about 220 mg to about 700 mg, about 230 mg to about 700 mg, about 240 mg to about 700 mg, about 250 mg to about 700 mg, about 260 mg to about 700 mg, about 270 mg to about 700 mg, about 280 mg to about 700 mg, about 290 mg to about 700 mg, about 300 mg to about 700mg, about 310mg to about 700mg, about 320mg to about 700mg, about 330mg to about 700mg, about 340mg to about 700mg, about 350mg to about 700mg, about 360mg to about 700mg, about 37 0mg to about 700mg, about 380mg to about 700mg, about 390mg to about 700mg, about 400mg to about 700mg, about 410mg to about 700mg, about 420mg to about 700mg, about 430mg to about 700m g, about 440mg to about 700mg, about 450mg to about 700mg, about 460mg to about 700mg, about 470mg to about 700mg, about 480mg to about 700mg, about 490mg to about 700mg, about 500mg to Approximately 700 mg, approximately 510 mg to approximately 700 mg, approximately 520 mg to approximately 700 mg, approximately 530 mg to approximately 700 mg, approximately 540 mg to approximately 700 mg, approximately 550 mg to approximately 700 mg, approximately 560 mg to approximately 700 mg, approximately 5 70 mg to about 700 mg, about 580 mg to about 700 mg, about 590 mg to about 700 mg, about 600 mg to about 700 mg, about 610 mg to about 700 mg, about 620 mg to about 700 mg, about 630 mg to about 700 mg, about 640 mg to about 700 mg, about 650 mg to about 700 mg, about 660 mg to about 700 mg, about 670 mg to about 700 mg, about 680 mg to about 700 mg, or about 690 mg to about 700 mg.

[0143] In some embodiments, the dose of the inositol phosphate of the present invention (e.g., myo-inositol hexaphosphate) is about 200 mg to about 210 mg, about 200 mg to about 220 mg, about 200 mg to about 230 mg, about 200 mg to about 240 mg, about 200 mg to about 250 mg, about 200 mg to about 260 mg, about 200 mg to about 270 mg, about 200 mg to about 280 mg, about 200 mg to about 290 mg, about 200 mg to about 300mg, about 200mg to about 310mg, about 200mg to about 320mg, about 200mg to about 330mg, about 200mg to about 340mg, about 200mg to about 350mg, about 200mg to about 360mg, about 20 0mg to about 370mg, about 200mg to about 380mg, about 200mg to about 390mg, about 200mg to about 400mg, about 200mg to about 410mg, about 200mg to about 420mg, about 200mg to about 430m g, about 200mg to about 440mg, about 200mg to about 450mg, about 200mg to about 460mg, about 200mg to about 470mg, about 200mg to about 480mg, about 200mg to about 490mg, about 200mg to Approximately 500mg, approximately 200mg to approximately 510mg, approximately 200mg to approximately 520mg, approximately 200mg to approximately 530mg, approximately 200mg to approximately 540mg, approximately 200mg to approximately 550mg, approximately 200mg to approximately 560mg, approximately 2 200mg to about 570mg, about 200mg to about 580mg, about 200mg to about 590mg, about 200mg to about 600mg, about 200mg to about 610mg, about 200mg to about 620mg, about 200mg to about 630mg, about 200mg to about 640mg, about 200mg to about 650mg, about 200mg to about 660mg, about 200mg to about 670mg, about 200mg to about 680mg, or about 200mg to about 690mg.

[0144] In some embodiments, a dose of an inositol phosphate (e.g., myo-inositol hexaphosphate) of the present invention is administered once daily (i.e., as a single daily administration). In some embodiments, the daily dose can be divided into smaller doses and administered separately. Thus, in some embodiments, the total daily dose can be divided into two, three, four, or more sub-doses (i.e., multiple daily administrations).

[0145] In some embodiments, a dose of an inositol phosphate (e.g., myo-inositol hexaphosphate) of the present invention is administered at least once a week. In some embodiments, a dose of an inositol phosphate (e.g., myo-inositol hexaphosphate) of the present invention is administered at least two, at least three, at least four, at least five, at least six, or at least seven times a week.

[0146] In some embodiments, the dose of inositol phosphates of the present invention (e.g., myo-inositol hexaphosphate) is administered for at least 1 week. In some embodiments, the dose of inositol phosphates of the present invention is administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, about 60 weeks, about 61 weeks, about 62 weeks, about 63 weeks, about 64 weeks, about 65 weeks, about 66 weeks, about 67 weeks, about 68 weeks, about 69 weeks, about 70 weeks, about 71 weeks, about 72 weeks, about 73 weeks, about 74 weeks, about 75 weeks, about 76 weeks, about 77 weeks, weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, or about 52 weeks.

[0147] In some embodiments, the dose of inositol phosphates (e.g., myo-inositol hexaphosphate) of the present invention is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, at least The dose may be administered for 25 weeks, at least 26 weeks, at least 27 weeks, at least 28 weeks, at least 29 weeks, at least 30 weeks, at least 31 weeks, at least 32 weeks, at least 33 weeks, at least 34 weeks, at least 35 weeks, at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, at least 48 weeks, at least 49 weeks, at least 50 weeks, at least 51 weeks, or at least 52 weeks.

[0148] In some embodiments, the dose of an inositol phosphate of the invention (e.g., myo-inositol hexaphosphate) is between 1 week and 4 weeks, between 1 week and 8 weeks, between 1 week and 12 weeks, between 1 week and 16 weeks, between 1 week and 20 weeks, between 1 week and 24 weeks, between 1 week and 28 weeks, between 1 week and 32 weeks, between 4 weeks and 8 weeks, between 4 weeks and 12 weeks, between 4 weeks and 16 weeks, between 4 weeks and 20 weeks, between 4 weeks and 24 weeks, between 4 weeks and 28 weeks, between 4 weeks and 32 weeks, between 8 weeks and 12 weeks, between 8 weeks and 16 weeks, between 8 weeks and 20 weeks, between 8 weeks and 24 weeks, between 8 weeks and 28 weeks, It is administered for weeks, 8 to 32 weeks, 12 to 16 weeks, 12 to 20 weeks, 12 to 24 weeks, 12 to 28 weeks, 12 to 32 weeks, 16 to 20 weeks, 16 to 24 weeks, 16 to 28 weeks, 16 to 32 weeks, 20 to 24 weeks, 20 to 28 weeks, 20 to 32 weeks, 24 to 28 weeks, 24 to 32 weeks, 28 to 32 weeks, 32 to 36 weeks, 36 to 40 weeks, 40 to 44 weeks, 44 to 48 weeks, or 48 to 52 weeks.

[0149] In detailed embodiments, the inositol phosphate dose of the invention (e.g., a 300 mg or 600 mg dose of myo-inositol hexaphosphate) is administered three times per week. In detailed embodiments, the inositol phosphate dose of the invention (e.g., a 300 mg or 600 mg dose of myo-inositol hexaphosphate) is administered three times per week for at least 12 weeks, at least 24 weeks, at least 42 weeks, or at least 52 weeks.

[0150] Alternatively, the compound, pharmaceutical composition or combined preparation can be administered as a component of a hemodialysis, hemofiltration, or peritoneal dialysis solution or system. In the particular case of patients treated by dialysis, a very suitable method of administration consists of administering the inositol phosphates of the invention (e.g., non-bolus administration) through a dialysis machine (pre- or post-filtration) instead of injecting them directly intravenously into the patient. Thus, the blood can be treated with the inositol phosphates of the invention (e.g., myo-inositol hexaphosphate) when circulated through the dialysis circuit while the patient is undergoing dialysis, and when blood containing the inositol phosphates of the invention is returned to the body.

[0151] Thus, in some embodiments, the compound, pharmaceutical composition, or combined preparation defined in any of the above-disclosed embodiments is administered to a patient during hemodialysis. In some embodiments, the compound, pharmaceutical composition, or combined preparation defined in any of the above-disclosed embodiments is administered to the blood extracted from the patient during hemodialysis, preferably before the blood is filtered (i.e., the therapeutic agent is administered to the patient's unfiltered blood in the dialysis circuit). In some embodiments, the compound is an inositol hexaphosphate, particularly myo-inositol hexaphosphate sodium salt, or a derivative thereof, i.e., R3 and R7 = a group of formula V, where R 13 is H, n is an integer from 2 to 200, and R1, R5, R9 and R 11 is all groups of formula II (or sodium salts thereof).

[0152] In the case of dialysis patients, administration of the inositol phosphates (e.g., myo-inositol hexaphosphate) of the present invention via a dialysis machine allows the blood to equilibrate with the dialysate before being returned to the body; thus, the inositol phosphates (e.g., myo-inositol hexaphosphate) of the present invention can capture ionized calcium, a fact that is compensated for when the blood passes through a dialysis filter, thereby eliminating the aforementioned side effects and significantly improving the safety profile. Furthermore, administering the inositol phosphates (e.g., myo-inositol hexaphosphate) of the present invention in conjunction with hemodialysis advantageously allows for reduced compound dosages and minimized adverse side effects, resulting in reduced toxicity, especially when administered to unfiltered blood extracted from the patient during hemodialysis.

[0153] In some embodiments, the compound, pharmaceutical composition or combined formulation defined in any of the above disclosed embodiments is administered to a patient being treated with hemodialysis before or after the dialysis treatment.

[0154] Indications The compounds, pharmaceutical compositions, combination formulations, methods, and routes of administration defined in any of the above-disclosed embodiments can be used to treat, inhibit the progression of, or prevent (a) cardiovascular calcification, or (b) a subject in need of treatment, inhibit the progression of, or prevent a disease, condition, or symptom associated with cardiovascular calcification, or (c) a subject at risk of developing said cardiovascular calcification, an associated disease, condition, or symptom. In some embodiments, the subject suffers from renal failure.

[0155] In some further embodiments, the compound, pharmaceutical composition, combined preparation, method and route of administration defined in any of the above-disclosed embodiments can be used for treating, inhibiting or preventing the progression of (a) coronary artery calcification, aortic calcification or aortic valve calcification, or (b) the disease, condition or symptom associated with coronary artery calcification, aortic calcification or aortic valve calcification, or (c) the subject who is at risk of developing coronary artery calcification, aortic calcification or aortic valve calcification, or the disease, condition or symptom associated with any of them.In some further embodiments, the pharmaceutical composition of the present invention is a combined preparation comprising at least one second active agent.In some embodiments, the subject suffers from renal failure.

[0156] In some embodiments, the renal disease in the subject can be acute, chronic, or both. In some embodiments, the subject is undergoing dialysis (e.g., peritoneal dialysis, hemodialysis). In a further aspect of this embodiment, the subject is undergoing hemodialysis. In other embodiments, the subject is not undergoing dialysis (e.g., a subject with CKD in stages 1-4).

[0157] The following embodiments further illustrate the scope of the invention. Embodiment 1. A compound of general formula I, or a pharmaceutically acceptable salt thereof, for use in treating, inhibiting the progression of, or preventing cardiovascular calcification, or a disease, condition, or symptom associated with cardiovascular calcification, in a subject in need thereof:

[0158] [ka]

[0159] [In the formula, (i) R1, R3, R5, R7, R9 and R 11 are independently selected from OH, groups of formula II, III, IV:

[0160] [ka]

[0161] and a heterologous moiety, (ii) R1, R3, R5, R7, R9 and R 11 at least one of which is selected from groups of formula II, III and IV, (iii) R1, R3, R5, R7, R9, and R 11 wherein 0, 1, 2, or 3 of the A compound of general formula I, or a pharmaceutically acceptable salt thereof, wherein: (a) the compound is in a form suitable for parenteral, topical, or enteral administration; and (b) the compound is administered to the subject in a non-bolus sustained release form at an effective dosage of about 200 mg to about 700 mg per administration. Embodiment 2. The heterologous moiety is selected from the group of formula V, the group of formula VI, and the group of formula VII:

[0162] [ka]

[0163] [In the formula, n is an integer ranging from 2 to 200, and R 13 is selected from H, methyl and ethyl. Embodiment 3. A compound according to embodiment 1 or 2, wherein the cardiovascular calcification is coronary artery calcification, aortic calcification, or aortic valve calcification. Embodiment 4. A compound according to any one of embodiments 1-3, wherein the compound of formula I is inositol hexaphosphate. Embodiment 5. A compound according to embodiment 4, wherein the inositol hexaphosphate is myo-inositol hexaphosphate. Embodiment 6. A compound according to embodiment 4 or 5, wherein the inositol hexaphosphate is in the form of its hexasodium salt. Embodiment 7. R1, R3, R5, R7, R9, and R 11The compound according to any one of embodiments 1 to 3, wherein one or two of are selected from groups of formulae V, VI and VII. Embodiment 8. R1, R5, R9 and R 11 A compound according to embodiment 7, wherein R is a group of formula II and R and R are groups of formula V. Embodiment 9. The group of formula V is a group in which n is in the range of 2 to 200 and R 13 is H. Embodiment 10. A pharmaceutical composition for use in treating, inhibiting the progression of, or preventing cardiovascular calcification in a subject in need thereof, comprising a compound according to any one of embodiments 1 to 9 and a pharmaceutically acceptable excipient and carrier. Embodiment 11. A compound according to any one of embodiments 1 to 9 or a pharmaceutical composition according to embodiment 10, wherein the subject has renal failure. Embodiment 12. A compound according to any one of embodiments 1 to 9 or a pharmaceutical composition according to embodiment 10, wherein the subject is undergoing dialysis. Embodiment 13. A compound or pharmaceutical composition according to any one of embodiments 1 to 12, wherein parenteral administration is intravenous, subcutaneous, intramuscular, or by intravenous infusion. Embodiment 14. The compound or pharmaceutical composition according to embodiment 13, wherein the intravenous infusion is carried out using a dialysis machine. Embodiment 15. A compound or pharmaceutical composition according to any one of embodiments 1 to 14, wherein the subject is a human. Embodiment 16. The compound or pharmaceutical composition according to any one of embodiments 1 to 15, wherein the compound is administered to the subject at a dosage of about 250 mg to about 650 mg per administration to the subject. Embodiment 17. The compound or pharmaceutical composition according to any one of embodiments 1 to 17, wherein the compound is administered to the subject at a dosage of about 300 mg to about 600 mg per administration to the subject. Embodiment 18. The compound or pharmaceutical composition according to any one of embodiments 1 to 17, wherein the compound is administered to the subject at a dosage of about 350 mg to about 550 mg per administration to the subject. Embodiment 19. A compound or pharmaceutical composition according to any one of embodiments 1 to 18, wherein the dosage is administered in a single daily dose. Embodiment 20. A compound or pharmaceutical composition according to any one of embodiments 1 to 18, wherein the dosage is administered in multiple daily doses. Embodiment 21. A compound or pharmaceutical composition according to any one of embodiments 1 to 20, wherein the dosage is administered at least once a week. Embodiment 22. A compound or pharmaceutical composition according to any one of embodiments 1 to 21, wherein the dosage is administered 2, 3, 4, 5, 6 or 7 times per week. Embodiment 23. A compound or pharmaceutical composition according to any one of embodiments 1 to 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 to 23, wherein the dosage is administered for about 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. Embodiment 25. A compound or pharmaceutical composition according to any one of embodiments 1 to 24, wherein the dosage is administered for at least 12 weeks. Embodiment 26. A compound or pharmaceutical composition according to any one of embodiments 1 to 25, wherein the dosage is administered for at least 24 weeks. Embodiment 27. A compound or pharmaceutical composition according to any one of embodiments 1 to 26, wherein the dosage is administered for at least 42 weeks. Embodiment 28. A compound or pharmaceutical composition according to any one of embodiments 1 to 27, wherein the dosage is administered for at least 52 weeks. Embodiment 29. A combined preparation comprising (a) a compound according to any one of embodiments 1 to 9 or a pharmaceutical composition according to embodiment 10 and (b) at least one second active agent. Embodiment 30. A combination formulation according to embodiment 29, wherein the second active agent is selected from the group consisting of vitamins, calcimimetics, bisphosphonates, phosphate binders, thiosulfates, pyrophosphates, citrates, diuretics, antihypertensives, cholesterol-lowering agents, phosphodiesterase inhibitors, and combinations thereof. Embodiment 31. A combination formulation according to embodiment 30, wherein the vitamin is vitamin B, vitamin D, vitamin K, or a combination thereof. Embodiment 32. The combination formulation according to embodiment 30, wherein the calcimimetics is cinacalcet ((R)—N-[1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine, KAI-4169 (etelcalcetide), NPS R-467 (((R)—N-(3-phenylpropyl)-1-(3-methoxyphenyl)ethylamine)), NPS R-568 ((R)-2-chloro-N-(1-(3-methoxyphenyl)ethyl)benzenepropanamine), or a combination thereof. Embodiment 33. A combination formulation according to embodiment 30, wherein the phosphate binder is a calcium salt, iron salt, lanthanum salt, aluminum salt, magnesium salt, sevelamer salt, or a combination thereof. Embodiment 34. A combination formulation according to embodiment 30, wherein the bisphosphonate is etidronate, alendronate, risedronate, zoledronate, tiludronate, pamidronate, monidronate, neridronate, palnidronate, olpadronate, clodronate, ibandronate, or a combination thereof. Embodiment 35. A combination formulation according to embodiment 30, wherein the phosphodiesterase inhibitor is cilostazol, pentoxifylline, or a combination thereof. Embodiment 36. A combination formulation according to any one of embodiments 29 to 35, wherein (a) a compound according to any one of embodiments 1 to 9 or a pharmaceutical composition according to embodiment 10 and (b) a second active agent are administered separately, simultaneously or sequentially.

[0164] This invention is further illustrated by the following examples, which should not be construed as limiting. The contents of all references cited throughout this application are hereby incorporated by reference in their entirety.

[0165] Example 1 Slowing the progression of cardiovascular calcification with SNF472 in patients undergoing hemodialysis: Results of a randomized, phase 2b clinical trial High cardiovascular morbidity and mortality in patients with end-stage kidney disease (ESKD) can be attributed in part to extensive cardiovascular calcification (CVC). SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits hydroxyapatite formation and growth.

[0166] This double-blind, placebo-controlled phase 2b study compared the progression of coronary artery calcium (CAC) volume scores by CT scan and other measures of CVC during 52 weeks of treatment with SNF472 or placebo in addition to standard therapy in adult patients with ESKD undergoing hemodialysis. Patients were randomized 1:1:1 to receive SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) administered via infusion into the hemodialysis line three times weekly during hemodialysis sessions. The primary endpoint was the change in log CAC volume score from baseline through week 52. The primary efficacy analysis combined SNF472 treatment arms and included all patients in the modified intention-to-treat (mITT) population who received at least one dose of SNF472 or placebo and had one evaluable post-baseline CT scan. Missing data were imputed by last observation (LOCF) in the primary analysis. The per-protocol analysis included all patients with an evaluable scan at Week 52 and 80% exposure to study drug. The mean change in log CAC volume score was 11% (95% CI, 7% to 15%) in the combined SNF472 dose group and 20% (95% CI, 14% to 26%) in the placebo group (P = 0.016) in the primary analysis (mITT LOCF). The mean change in log CAC volume score was 8% (95% CI, 4% to 12%) in the combined SNF472 dose group and 24% (95% CI, 16% to 32%) in the placebo group (P = 0.001) in the primary per-protocol (PP) analysis.

[0167] Compared with placebo (mITT LOCF), SNF472 significantly attenuated the progression of calcium volume score in the aortic valve (14% [95% CI, 5% to 24%] vs. 98% [95% CI, 77% to 123%], P<0.001). The median change from baseline in thoracic aortic volume score was 234 for placebo and 125 for the combined SNF472 dose groups.

[0168] Deaths 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 SNF472 300 mg, SNF472 600 mg, and placebo, respectively. Most adverse events were mild. Adverse events led to discontinuation in 14%, 29%, and 20% of patients treated with SNF472 300 mg, SNF472 600 mg, and placebo, respectively.

[0169] Thus, compared with placebo, SNF472 significantly attenuated the progression of CAC and aortic valve calcification in patients with ESKD receiving hemodialysis in addition to standard care.

[0170] material and method Study design and participants This multinational, randomized, placebo-controlled, double-blind phase 2b study was conducted among adult patients (18-80 years old) undergoing hemodialysis for ≥6 months who had a coronary artery calcium (CAC) Agatston score of 100-3500 units at study entry, as measured by non-contrast multidetector-row computed tomography (MDCT). The calcium Agatston score was used for study eligibility because it is commonly used for risk stratification in clinical practice. Younger patients (18-54 years old) were also required to have a history of diabetes (type 1 or type 2). The main exclusion criteria were planned kidney transplantation, weight greater than 136 kg, recent hospitalization (within 3 months) for a cardiovascular event (unstable angina, myocardial infarction, stroke, transient ischemic attack, amputation, peripheral or coronary artery bypass surgery, or unstable heart failure), hypocalcemia (serum calcium <8.0 mg / dL [2.0 mmol / L]), extremely elevated serum phosphate (>10 mg / dL [3.23 mmol / L] within the last 2 months), uncontrolled hypertension (diastolic blood pressure >100 mm Hg after two or more consecutive dialysis sessions within the last 2 months), or an investigator-perceived expected survival of <2 years.

[0171] After screening, eligible patients were randomized 1:1:1 to receive SNF472 300 mg, SNF472 600 mg, or placebo three times weekly, infused over 2.5 ± 0.5 hours during each hemodialysis session for 52 weeks.

[0172] To maintain blinding, randomization was performed using a centralized electronic randomization system, and the study medication was packaged in identical vials containing SNF472 or saline. Randomization was stratified by baseline CAC Agatston score (100 to <399, 400 to 1000, or >1000 U). Investigators controlled blood pressure, calcium, phosphate, parathyroid hormone, lipids, and anemia according to current guidelines or standard practices at the investigator's institution.

[0173] At screening and week 52 (or early discontinuation), imaging of the coronary arteries, aortic valve, and thoracic aorta was performed using multidetector computed tomography (MDCT) with a minimum of 64 scans. A core expert blinded to the patient's treatment group reviewed each scan and quantified each calcified area using 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 postrandomization scan was considered evaluable if an experienced image reviewer deemed it of sufficient quality to compare with the baseline scan and could calculate a CAV volume score without artifact. Patients who discontinued before week 52 without consent to discontinue were asked to undergo a CT scan for efficacy assessment to maximize available follow-up and minimize missing data.

[0174] endpoint The primary efficacy endpoint was the change from baseline to week 52 in the log CAC volume score, which has known lower variability than the Agatston score (Callister, 2008, supra). The primary efficacy analysis combined the two SNF472 treatment groups compared to placebo. Secondary efficacy endpoints included the change from baseline to week 52 in the log CAC Agatston score, the change from baseline to week 52 in the log calcium volume score and log calcium Agatston score at the aortic valve and thoracic aorta levels, and the proportion of patients with a progression of <15% in the CAC Agatston score at week 52 (Budoff M et al., JACC Cardiovasc Imaging 2010;3:1229-1236). Each endpoint was analyzed for the combined SNF472 dose groups versus placebo and for each SNF472 dose group versus placebo. Other endpoints included cardiovascular outcomes (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or heart failure), all-cause mortality, incidence of adverse events (overall, serious, or leading to discontinuation of study drug), and a composite safety endpoint of changes from baseline through week 52 in laboratory tests.

[0175] statistical analysis Analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, 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 underwent a post-randomization CT scan with CAC volume score. For the primary analysis of calcification progression at week 52, the look-forward (LOCF) to the last observation (post-randomization scan) in the mITT population was used.

[0176] The primary efficacy analysis model was an analysis of covariance (ANCOVA) with change in log score (log [Week 52] - log [Baseline]) as the dependent variable and a fixed response period for the randomized treatment group and log (Baseline) as the covariate; the model was stratified by baseline CAC Agatston score. The primary comparison of interest was the SNF472 combination dose group versus placebo; supportive comparisons examined differences between each dose and placebo.

[0177] Geometric least squares (LS) means and 95% confidence intervals (CIs) were estimated and back-transformed before publication to generate mean percent changes from baseline by week 52. For each comparison between SNF472 and placebo, geometric LS means and 95% CIs for treatment differences were calculated. A two-sided p-value of <0.05 was considered statistically significant. For secondary efficacy endpoints, we used similar ANCOVA models to compare the NF472 combination dosage group versus placebo and the SNF472 300 mg and 600 mg doses versus placebo separately. Zero calcium scores for the aortic valve and thoracic aorta were imputed with the following minimum values ​​in the relevant treatment arms:

[0178] For the primary analysis of calcification progression at week 52, last observation carried forward (LOCF) was used. Subsequent sensitivity analyses performed multiple imputation to explore the effect of missing values ​​for patients who discontinued the study early. If patients had only a screening CAC volume score, no imputation was performed. The first multiple imputation imputed missing values ​​in each group using the distribution induced by non-missing patient data for that group. The second multiple imputation imputed missing values ​​for the entire group using the distribution induced by non-missing patient data in the placebo arm.

[0179] For the composite safety endpoint to compare SNF472 with placebo, proportional hazards (Cox) regression was used, stratified by baseline CAC Agatston score. The planned sample size of 270 patients provided 80% power to test the hypothesis that the log-transformed true difference in progression between the SNF472 combination and placebo groups was 0.130, corresponding to a true ratio of 1.139, or 18.5% progression in the SNF472 combination group and 35% progression in the placebo group.

[0180] result Registration and Placement Of 645 patients from 65 centers screened for enrollment, 274 patients were randomized to one of three treatment groups: SNF472 300 mg (n = 92), SNF472 600 mg (n = 91), or placebo (n = 91). Reasons for study discontinuation before week 52 were similar across treatment groups. Safety evaluations included 92, 91, and 90 patients in the SNF472 300 mg, SNF472 600 mg, and placebo groups, respectively, who received at least one dose of study drug (Figure 7). Follow-up CT scans were available for assessment of calcium volume score progression in the mITT population for 142 patients in the NF472 combination dosing group and 77 patients in the placebo group.

[0181] Baseline characteristics After the randomization codes were unblinded for this analysis, baseline patient demographic and clinical characteristics were shown to be similar across the three treatment groups. At baseline, the geometric mean scores were 621, 636, and 634 units for the CAC Agatston score and 573, 583, and 584 for the CAC volume score in the SNF472 300 mg, SNF472 600 mg, and placebo groups, respectively. Baseline calcium scores for the coronary arteries and aortic valve are summarized by treatment group in Table 1.

[0182] [Table 1]

[0183] coronary artery For the primary endpoint, SNF472 (combination group) significantly attenuated CAC progression compared with placebo; the mean change in CAC volume score from baseline to week 52 was 11% (95% CI, 7% to 15%) and 20% (95% CI, 14% to 26%), respectively (P = 0.016; Figure 8A). The mean change from baseline in CAC volume score to week 52 was 12% (95% CI, 6% to 18%) in the 300 mg dose group (P = 0.052 vs. placebo) and 10% (95% CI, 4% to 17%) in the 600 mg dose group (P = 0.029 vs. placebo) (Figure 11A).

[0184] Corresponding results using CAC Agathaton scores showed a mean change of 11% (95% CI, 6%-17%) for the SNF472 combination group and 20% (95% CI, 12%-28%) for placebo (P = 0.075; Figure 8B). The mean change in CAC Agathaton scores was 10% (95% CI, 3%-17%) for the 300 mg dose group (P = 0.055 vs. placebo) and 13% (95% CI, 6%-22%) for the 600 mg dose group (P = 0.24 vs. placebo) (Figure 11B).

[0185] Some positive results for calcium volume and Agatston score progression were obtained in the per-protocol population of patients who completed 52 weeks of treatment (Figures 9A and 9B) and in a sensitivity analysis using multiple imputation for missing values ​​in the mITT population (Figures 12A and 12B).

[0186] The proportion of patients with CAC Agatston progression <15% at week 52 was 61% in the SNF472 combination group and 48% in the placebo group in the mITT population (P=0.030; Figure 10A), and 64% and 43%, respectively, in the per-protocol population (P=0.002; Figure 10B).

[0187] aortic valve The change from baseline in aortic valve calcium volume score to week 52 was 14% (95% CI, 5% to 24%) in the SNF472 combination group and 98% (95% CI, 77% to 123%) in the placebo group (P<0.001; Fig. 8C). The mean change from baseline to week 52 was 28% (95% CI, 14% to 43%) in the 300 mg dose group (P<0.001 vs. placebo) and 1% (95% CI, -10% to 14%) in the 600 mg dose group (P<0.001 vs. placebo) (Fig. 11C).

[0188] Corresponding results for calcium Agathaton scores were 14% (95% CI, 2% to 28%) in the SNF472 combination group and 186% (95% CI, 145% to 235%) in the placebo group (P<0.001; Fig. 8D). The mean change from baseline to week 52 was 33% (95% CI, 14% to 54%) in the 300 mg dose group (P<0.001 vs. placebo) and -2% (95% CI, -16% to 16%) in the 600 mg dose group (P<0.001 vs. placebo) (Fig. 11D).

[0189] Similar results for calcium volume and Agatston score progression were obtained in sensitivity analyses using multiple imputation for missing values ​​in the mITT population (FIGS. 12C and 12D). thoracic aorta The change from baseline in thoracic aorta calcium volume score to week 52 was 23% (95% CI, 16% to 30%) in the SNF472 combination group and 28% (95% CI, 19% to 38%) in the placebo group (P = 0.40; Figure 8E). The mean change from baseline to week 52 was 25% (95% CI, 16% to 35%) in the 300 mg dose group (P = 0.63 vs. placebo) and 21% (95% CI, 11% to 32%) in the 600 mg dose group (P = 0.34 vs. placebo) (Figure 11E).

[0190] Corresponding results for calcium Agathaton scores were 29% (95% CI, 20% to 38%) in the NF472 combination group and 32% (95% CI, 21% to 45%) in the placebo group (P = 0.66; Figure 8F). The mean change from baseline to week 52 was 30% (95% CI, 19% to 43%) in the 300 mg dose group (P = 0.82 vs. placebo) and 28% (95% CI, 15% to 42%) in the 600 mg dose group (P = 0.61 vs. placebo) (Figure 11F).

[0191] Similar results for calcium volume and Agatston score progression were obtained in sensitivity analyses using multiple imputation for missing values ​​in the mITT population (Figures 12E and 12F). The median change from baseline in thoracic aortic volume score was 204 for placebo and 131 for the combined SNF472 dose group (mITT LOCF), representing a difference of 35.8%. The median change from baseline in thoracic aortic volume score was 234 for placebo and 125 for the combined SNF472 dose group (PP), representing a difference of 46.6%.

[0192] Composite Safety Endpoint The incidence of the composite safety endpoint in the SNF472 300 mg, SNF472 600 mg, and placebo groups was 8%, 7%, and 11%, respectively (Table 2). The hazard ratio for the composite safety endpoint in the SNF472 combination group versus placebo was 0.60 (95% CI, 0.26 to 1.37; P = 0.22).

[0193] [Table 2]

[0194] Adverse events Adverse events occurred in 79 of 92 patients (86%) in the SNF472 300 mg group, 84 of 91 patients (92%) in the SNF472 600 mg group, and 78 of 90 patients (87%) in the placebo group. Serious adverse events occurred in 38 patients (41%) in the SNF472 300 mg group, 55 patients (60%) in the SNF472 600 mg group, and 49 patients (54%) in the placebo group.

[0195] Adverse events led to study drug discontinuation in 13 patients (14%) in the SNF472 300 mg group, 26 patients (29%) in the SNF472 600 mg group, and 18 patients (20%) in the placebo group. The majority of these discontinuations were due to renal transplantation in 27 patients overall (SNF472 300 mg 6%; SNF472 600 mg 12%; and placebo 9%). No other events led to study drug discontinuation in more than one patient.

[0196] No clinically significant abnormalities were identified from analysis of clinical laboratory values ​​(hematology and chemistry) with SNF472 compared to placebo. Deaths occurred in one patient in the SNF472 300 mg group (multiple organ dysfunction), six patients in the SNF472 600 mg group (due to aortic stenosis, arteriosclerosis, hypotension, cardiac arrest, septic shock, and epilepsy, respectively), and five patients in the placebo group (due to congestive heart failure, multiple organ dysfunction, sepsis, postprocedural complications, and renal transplant, respectively). None of the deaths were considered related to the study drug.

[0197] Consideration This international, multicenter, randomized, double-blind, placebo-controlled clinical trial demonstrated that SNF472, a selective inhibitor of hydroxyapatite crystal formation and growth, attenuated the progression of coronary artery and aortic valve calcification compared with placebo when infused during each hemodialysis session for one year. These results are surprising given the concurrent use of drugs previously shown to potentially attenuate CAC, such as the non-calcium phosphate binder sevelamer and the calcimimetic drug 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;18:582-588). In those prior trials, patients undergoing hemodialysis who were assigned to placebo showed a mean rate of CAC progression of 35-40% per year, nearly double the rate of progression seen in placebo-treated patients in this study. The intended power calculation for the study assumed a CAC volume score progression of 18.5% for patients treated with SNF472 and 35% for patients treated with placebo (a relative difference in progression of 47%). These assumptions were based on prior published rates of progression. Although the observed progression of CAC in placebo-treated patients in this study was slower than expected, due in part to the use of non-calcium phosphate binders and calcimimetics in many patients, the 45% relative difference was very close to the study's original expectations.

[0198] At baseline, all patients had coronary artery calcium with a CAC Agatston score of 100 to 3500 units. Furthermore, 57% of patients had aortic valve calcification (Bellasi, 2019, supra). Because the primary objective of this study was to demonstrate that SNF472 effectively inhibits the progression of coronary artery calcification, patients with moderate to high CAC scores were enrolled, as these patients typically exhibit a more rapid progression of calcification.

[0199] Previous meta-analyses have shown that the prescription of non-calcium phosphate binders is associated with attenuation of cardiovascular calcification progression and 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 prior publications. As a result, CAC is recognized as a risk-modifying marker in the latest guidelines from the American Heart Association and the American College of Cardiology for primary prevention of atherosclerotic cardiovascular disease. Furthermore, simple measures of CAC and calcification measured by CT, such as radial and femoral artery and aortic calcification seen on plain x-rays, have been shown to be strongly associated with adverse events in ESKD (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).

[0200] It is well established that patients with ESKD develop cardiovascular calcification significantly more frequently than patients with normal or near-normal renal function, and that there are two distinct sites of arterial calcification in these patients: intimal and medial. The former is associated with traditional risk factors for atherosclerosis and inflammation, while the latter is found primarily (if not exclusively) in medium- and large-caliber arteries and is more closely associated with bone mineral metabolism disorders specific to ESKD. Calcification of medium- and large-sized arterial grafts contributes to reduced vascular compliance, which may induce left ventricular hypertrophy and systolic / diastolic dysfunction over the long term. Reduced compliance, as measured by increased pulse pressure velocity, can lead to reduced diastolic filling of coronary arteries in conditions of associated myocardial ischemia, even in the absence of obstructive luminal disease. Therefore, arterial calcification in ESKD should be interpreted as a precursor to severe complications and, therefore, is worthy of therapeutic target pursuit. Equally important is the impact of cardiac valve calcification, particularly aortic valve calcification, in ESKD (Marwick T et al., Kidney Int. 2019;96:836-849). Many patients develop severe calcification of the left heart valve with subsequent regurgitation or restriction of valve leaflet mobility. These conditions are associated with progressive left ventricular fibrosis, left ventricular hypertrophy and dysfunction, as well as endocarditis and severe conduction abnormalities. Furthermore, surgical and interventional treatments proven effective in the general population fail to provide similar benefits in patients with ESKD. Therefore, the significant reduction in aortic valve calcification progression seen in this study is encouraging.

[0201] Regardless of the pathophysiology of cardiovascular calcification, the final step involves the formation of hydroxyapatite crystals through an active process that mimics bone formation. In this regard, SNF472 is a specific inhibitor of hydroxyapatite crystallization and is effective in slowing the progression of coronary artery and aortic valve calcification.

[0202] conclusion Compared with placebo, treatment with SNF472 significantly attenuated the progression of coronary artery and aortic valve calcification at 52 weeks in patients with ESKD undergoing hemodialysis. These results are obtained against the backdrop of frequent use of drugs capable of attenuating, at least partially, the progression of cardiovascular calcification in patients with ESKD. The claims as filed are as follows: [Claim 1] 1. A compound of general formula I, or a pharmaceutically acceptable salt thereof, for use in treating, inhibiting the progression of, or preventing cardiovascular calcification, or a disease, condition, or symptom associated with cardiovascular calcification, in a subject in need thereof: [ka] [In the formula, (i) R1, R3, R5, R7, R9 and R 11 are independently selected from OH, groups of formula II, III, IV: [ka] and a heterologous moiety, (ii) R1, R3, R5, R7, R9 and R 11 at least one of which is selected from groups of formulas II, III and IV; (iii) R1, R3, R5, R7, R9, and R 11 wherein 0, 1, 2 or 3 of are heterologous moieties; (a) the compound is in a form suitable for parenteral, topical, or enteral administration; and (b) the compound is administered to the subject in a non-bolus sustained release form at an effective dosage of about 200 mg to about 700 mg per dose. [Claim 2] The heterologous moiety is selected from the group of formula V, the group of formula VI and the group of formula VII: [ka] [In the formula, n is an integer ranging from 2 to 200, R 13 is selected from H, methyl and ethyl. [Claim 3] 3. The compound according to claim 1 or 2, wherein the cardiovascular calcification is coronary artery calcification, aortic calcification, or aortic valve calcification. [Claim 4] 4. The compound of any one of claims 1 to 3, wherein the compound of formula I is inositol hexaphosphate. [Claim 5] 5. The compound of claim 4, wherein the inositol hexaphosphate is myo-inositol hexaphosphate. [Claim 6] 6. The compound of claim 4 or 5, wherein the inositol hexaphosphate is in the form of its hexasodium salt. [Claim 7] R1, R3, R5, R7, R9, and R 11 4. The compound according to claim 1, wherein one or two of: [Claim 8] R1, R5, R9 and R 11 8. The compound of claim 7, wherein R is a group of formula II and R and R are groups of formula V. [Claim 9] The group of formula V has n in the range of 2 to 200, and R 13 The compound of claim 8, wherein is H. [Claim 10] 10. A pharmaceutical composition comprising a compound of any one of claims 1 to 9 and pharmaceutically acceptable excipients and carriers for use in treating, inhibiting the progression of, or preventing cardiovascular calcification in a subject in need thereof. [Claim 11] Cardiovascular calcification in a subject in need of treatment, inhibition of progression, or prevention. A pharmaceutical composition comprising myo-inositol hexaphosphate and a pharmaceutically acceptable excipient and carrier for use in treating, inhibiting the progression of, or preventing calcification. [Claim 12] 12. The compound of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 or 11, wherein the subject suffers from renal failure. [Claim 13] 12. The compound of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 or 11, wherein the subject is undergoing dialysis. [Claim 14] 14. The compound or pharmaceutical composition according to any one of claims 1 to 13, wherein parenteral administration is intravenous, subcutaneous, intramuscular or by intravenous infusion. [Claim 15] 15. The compound or pharmaceutical composition of claim 14, wherein the intravenous infusion is performed using a dialysis machine. [Claim 16] 16. The compound or pharmaceutical composition of any one of claims 1 to 15, wherein the subject is a human. [Claim 17] 17. The compound or pharmaceutical composition of any one of claims 1 to 16, wherein the compound is administered to the subject at a dose of about 250 mg to about 650 mg per administration to the subject. [Claim 18] 18. The compound or pharmaceutical composition according to any one of claims 1 to 17, wherein the compound is administered to the subject at a dose of about 300 mg to about 600 mg per administration to the subject. [Claim 19] 19. The compound or pharmaceutical composition of any one of claims 1 to 18, wherein the compound is administered to the subject at a dosage of about 350 mg to 550 mg per administration to the subject. [Claim 20] 20. The compound or pharmaceutical composition of any one of claims 1 to 19, wherein the dosage is administered in a single daily dose. [Claim 21] 21. The compound or pharmaceutical composition of any one of claims 1 to 20, wherein the dosage is administered in multiple doses daily. [Claim 22] 22. The compound or pharmaceutical composition of any one of claims 1 to 21, wherein said dosage is administered at least once a week. [Claim 23] 23. The compound or pharmaceutical composition of any one of claims 1 to 22, wherein the dosage is administered 2, 3, 4, 5, 6 or 7 times per week. [Claim 24] 24. The compound or pharmaceutical composition of any one of claims 1 to 23, wherein said dosage is administered for at least one week. [Claim 25] 25. The compound or pharmaceutical composition of any one of claims 1 to 24, wherein the dosage is administered for about 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. [Claim 26] A combined formulation comprising: (a) a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11; and (b) at least one second active agent.

Claims

1. Cardiovascular calcification, or angina, heart disease, coronary disease, electrocardiogram abnormalities, heart failure, congestive heart failure a disease associated with cardiovascular calcification selected from the group consisting of left ventricular hypertrophy, myocardial infarction, and myocardial ischemia in a human subject in need of treatment, inhibition of progression, or prevention of a disease, condition, or symptom, Treatment or inhibition of progression of cardiovascular calcification or diseases, conditions or symptoms associated with said cardiovascular calcification A pharmaceutical composition for the prevention or control of myo-inositol hexaphosphate or pharmaceutically acceptable salts thereof. including acceptable salts thereof, (a) the composition is in a form suitable for parenteral administration; and (b) the therapeutic, suppressive or In the prevention, the composition provides the myo-inositol hexaphosphate or pharmaceutically acceptable salt thereof. The salt thereof is administered in a non-bolus sustained release form at an effective dose of about 200 mg to about 700 mg per administration. The composition is administered to the subject in the form of a pharmaceutical composition.

2. The composition according to claim 1, wherein the cardiovascular calcification is aortic valve calcification.

3. 3. The composition of claim 1, comprising myo-inositol hexaphosphate hexasodium salt.

4. A method for treating, inhibiting the progression of, or preventing cardiovascular calcification in a human subject in need thereof. A compound according to any one of claims 1 to 3 for treating, inhibiting the progression of, or preventing vascular calcification. The pharmaceutical composition according to claim 1, wherein the composition comprises a pharmaceutically acceptable excipient and a carrier. The pharmaceutical composition.

5. A method for treating, inhibiting the progression of, or preventing cardiovascular calcification in a human subject in need thereof. Myo-inositol hexaphosphate or its derivatives for the treatment, inhibition of its progression, or prevention of vascular calcification or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising a pharmaceutically acceptable excipient and carrier. (a) the composition is in a form suitable for parenteral administration; and (b) the composition In the treatment, suppression or prevention, the composition provides the myo-inositol hexaphosphate or A pharmaceutically acceptable salt thereof is administered at an effective dose of about 200 mg to about 700 mg per administration. The pharmaceutical composition is administered to the subject in a bolus sustained release form.

6. 6. The pharmaceutical composition according to claim 5, wherein the cardiovascular calcification is aortic valve calcification. Pharmaceutical compositions.

7. The pharmaceutical composition of claim 1 , wherein the subject has renal failure.

8. The pharmaceutical composition of claim 1 , wherein the subject is undergoing dialysis.

9. 10. The method of claim 1, wherein parenteral administration is intravenous, subcutaneous, intramuscular, or by intravenous infusion.

9. The pharmaceutical composition according to any one of claims 8 to 8.

10. 10. The pharmaceutical composition of claim 9, wherein the intravenous infusion is performed using a dialysis machine.

11. the myo-inositol hexaphosphate or a pharmaceutically acceptable salt thereof is administered to the subject 10. The method of claim 1, wherein the subject is administered a dose of about 250 mg to about 650 mg per day. The pharmaceutical composition according to any one of the preceding claims.

12. the myo-inositol hexaphosphate or a pharmaceutically acceptable salt thereof is administered to the subject 11. The method of claim 1, wherein the subject is administered a dose of about 300 mg to about 600 mg per day. The pharmaceutical composition according to any one of the preceding claims.

13. the myo-inositol hexaphosphate or a pharmaceutically acceptable salt thereof is administered to the subject 13. The method of claim 1, wherein the subject is administered a dose of about 350 mg to 550 mg per day. The pharmaceutical composition described in any one of claims 1 to 4.

14. 14. The method of claim 1, wherein the dosage is administered in a single daily dose. Pharmaceutical compositions.

15. 14. The method of claim 1, wherein the dose is administered in multiple doses daily. Pharmaceutical compositions.

16. 16. The method of claim 1, wherein the dose is administered at least once a week. Pharmaceutical compositions.

17. 16. The method of claim 1, wherein the dose is administered 2, 3, 4, 5, 6, or 7 times per week. The pharmaceutical composition according to any one of claims 1 to 4.

18. 18. The method of claim 1, wherein the dose is administered for at least one week. Pharmaceutical compositions.

19. The dose is about 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、２ ８、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 of administration 18. The pharmaceutical composition according to any one of claims 1 to 17,

20. (a) a pharmaceutical composition according to any one of claims 1 to 4, and (b) at least one a combination formulation comprising a second active agent of the type The combined preparation is for the treatment, inhibition of progression, or prevention of cardiovascular calcification or a disease, condition, or symptom associated with cardiovascular calcification selected from the group consisting of angina pectoris, heart disease, coronary disease, electrocardiogram abnormalities, heart failure, congestive heart failure, left ventricular hypertrophy, myocardial infarction, and myocardial ischemia, in a human subject in need thereof.

21. The combination preparation described in claim 20, wherein the cardiovascular calcification is aortic valve calcification.

22. The combination formulation of claim 20 or 21, wherein the composition comprises myo-inositol hexaphosphate hexasodium salt.

23. A combination formulation according to any one of claims 20 to 22, wherein the combination formulation is for the treatment, inhibition of progression, or prevention of cardiovascular calcification in a human subject in need thereof, and the composition comprises pharmaceutically acceptable excipients and carriers.

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