WO2024023359A1 - Composés dérivés substitués en ip4-4,6 destinés à être utilisés dans le traitement, l'inhibition de la progression et la prévention de la calcification ectopique - Google Patents

Composés dérivés substitués en ip4-4,6 destinés à être utilisés dans le traitement, l'inhibition de la progression et la prévention de la calcification ectopique Download PDF

Info

Publication number
WO2024023359A1
WO2024023359A1 PCT/EP2023/071128 EP2023071128W WO2024023359A1 WO 2024023359 A1 WO2024023359 A1 WO 2024023359A1 EP 2023071128 W EP2023071128 W EP 2023071128W WO 2024023359 A1 WO2024023359 A1 WO 2024023359A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
aspects
calcification
myo
salt
Prior art date
Application number
PCT/EP2023/071128
Other languages
English (en)
Inventor
Mohamad Firas BASSISSI
Marc BLASCO FERRER
María Del Mar PÉREZ FERRER
Miquel David FERRER REYNÉS
Carolina Salcedo Roca
Alexander M. GOLD
Joan PERELLÓ BESTARD
Original Assignee
Sanifit Therapeutics, S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanifit Therapeutics, S.A. filed Critical Sanifit Therapeutics, S.A.
Publication of WO2024023359A1 publication Critical patent/WO2024023359A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • IP4-4,6 Substituted Derivative Compounds for Use in the Treatment, Inhibition of Progression, and Prevention of Ectopic Calcification
  • the present invention relates to IP4-4,6 substituted derivative compounds for use in the treatment, inhibition of progression, and prevention of (a) ectopic calcification and (b) diseases and/or conditions related to ectopic calcification.
  • Pharmaceutical and kits for such uses are also provided.
  • Ectopic calcification is defined as inappropriate biomineralization occurring in soft tissues (Cotran R, et al., Pathological Basis of Disease, 5th Ed., Robbins S, et al., Eds. (WB Saunders, Philadelphia, PA, US, 1994, pp 1-35).
  • EC is typically composed of calcium phosphate salts, including hydroxyapatite (HAP), but can also consist of calcium oxalates and octacalcium phosphate as seen in kidney stones (Pak C, Am J Kidney Dis 1991; 18:624-632).
  • EC may manifest independently on different locations, although it develops through similar mechanisms to physiological calcification (Giachelli C, Am J Pathol. 1999; 154(3):671-67).
  • the diversity of types of EC are believed to be related with having a chronic or a rare disease. See Fig. 1 (Kempf H, et al., Front Cell Dev Biol. 2021; 9:759702).
  • EC can be found in soft tissues such as vessels, heart valves, lungs, kidney, and brain. This pathological calcification leads to organ damage. Some of the most relevant pathologies associated to EC are listed below. See Table A.
  • Tissue repair response associated with inflammation and/or immunological responses e.g., calcinosis cutis
  • the most important of the extraosseous EC is that produced in the cardiovascular system, specifically in the arteries and heart valves, as it is a strong independent risk factor for increased mortality and cardiovascular events.
  • calcification is associated with CAD, atherosclerotic plaque burden, in peripheral vascular disease, and worse outcomes (e.g., increased risk of dissection) following angioplasty.
  • the valves are particularly prone to calcification.
  • Degenerative calcific aortic stenosis is currently the most common valvular lesion encountered in clinical cardiology and one of the most difficult to manage.
  • PAD-ESKD Peripheral Artery Disease
  • POD-ESKD end stage kidney disease
  • HAP calcium phosphate
  • gangrene gangrene
  • amputation A key etiological factor of PAD-ESKD is the accelerated deposition of calcium phosphate in the form of HAP in the media and intima of peripheral arteries in the lower extremities. This calcification causes narrowing and stiffening of arteries which results in reduction of arterial blood flow and distal ischemia.
  • Risk factors for PAD-ESKD include older age, diabetes, hypertension, and smoking (Chen J, etal., Nephrol Dial Transplant. 2016; 31 (7): 1145-1151).
  • the duration of dialysis is an important risk factor for PAD-ESKD and the risk factors of hypertension and diabetes are more prevalent and more difficult to control in patients with ESKD than in the general population (Rajagopalan S et al., Circulation 2006; 114(18): 1914-1922).
  • Patients with ESKD have been excluded from prior clinical studies of medical therapies for PAD and thus there are no approved therapies specifically for patients with PAD- ESKD.
  • the present invention discloses a compound of general formula I: a pharmaceutically acceptable salt thereof, or a combination thereof, wherein
  • R1, R3, R7, and R11 independently represent OPO3 2- ;
  • R5 and R9 are substituent groups each one corresponding to the formula -O-(alkyl)n-X, wherein n is an integer between 1 and 20, wherein the terminal group X is selected from the group consisting of -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, - NHCONRR', halogen, -CF3, alkyl, alkenyl, alkynyl, carbocycle (saturated or unsaturated), and heterocycle (saturated or unsaturated), and wherein R and R' are H or an alkyl group;
  • R5 and R9 are substituent groups each one corresponding to the formula -O-(alkyl) y -Cy-(alkyl
  • R1, R3, R7, and R11 independently represent OPO3 2- ;
  • R5 and R9 are substituent groups each one corresponding to the formula -O-(alkyl) y -A-(alkyl) y '-Z', wherein y and y' are an integer between 0 and 10, wherein A is a linker selected from the group consisting of -CONR-, -NHCOO-, -NHSO2, -NHCONR-, -NHCO-, and -OCONR, wherein the terminal group Z' is selected from the group consisting of -OR, -NRR', -COOR, - CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', carbocycle (saturated or unsaturated), heterocycle (saturated or unsaturated), and wherein R and R' are H or an alkyl group; and
  • the compound of formula I is an analog of (i), (ii) or (iii) wherein at least one of R1, R3, R7 or R11 is thiophosphate (-OPSO2 2- ) for use in the treatment, inhibition of progression, and prevention of ectopic calcification or the consequences thereof in a subject in need thereof.
  • the R5 and R9 substituent groups of the compound of formula I are identical. In some aspects, the R5 and R9 substituent groups of the compound of formula I are different.
  • the alkyl moiety in the R5 and R9 substituent groups includes at least one double or triple carbon bond, i.e., forming an alkenyl or alkynyl chain, respectively.
  • the alkenyl chains in the R5 and R9 substituent groups are identical.
  • the alkenyl chains in the R5 and R9 substituent groups are different.
  • the alkynyl chains in the R5 and R9 substituent groups are identical.
  • the alkynyl chains in the R5 and R9 substituent groups are different.
  • the alkyl moiety in the R5 and R9 substituent groups includes at least one double carbon bond and at least one triple carbon bond, forming a combination of an alkenyl and an alkynyl chain.
  • the combination of the alkenyl and the alkynyl chains in the R5 and R9 substituent groups is identical.
  • the combination of the alkenyl and the alkynyl chains in the R5 and R9 substituent groups is different.
  • the compound of formula I is selected from the group consisting of Compounds 1 to Compound 53.
  • the pharmaceutically acceptable salt is a sodium salt.
  • the sodium salt is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the sodium salt is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt.
  • the sodium salt is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I disclosed above and at least one pharmaceutically acceptable excipient or carrier.
  • the subject is human.
  • the administration is topical, enteral or parenteral.
  • the parenteral administration is intravenous.
  • the intravenous administration is by intravenous infusion.
  • the present invention also provides a kit or article of manufacture comprising at least one compound of formula I or a pharmaceutical composition comprising a compound of formula I and instructions for administration according to uses disclosed herein.
  • the kit or article of manufacture may also comprise at least one compound selected from the group consisting of the compounds listed in Table 1.
  • FIG. 1 is a simplified schematic representation of the cellular, extracellular, and systemic alterations related to ectopic calcification and their connection to some chronic ana rare diseases.
  • Fig. 2 is a simplified schematic representation of the physiochemical mechanism of action of the IP4-4,6 substituted derivatives of the present invention inhibiting the crystallization of hydroxyapatite (HAP) and thus being useful in the therapy of HAP- crystallization mediated diseases.
  • Fig. 3A and Fig. 3B present representative structures of Family A IP4-4,6 substituted derivative compounds (e.g., Compounds 1 to 30, and Compound 52 to 53).
  • Fig. 4A and Fig. 4B present representative structures of Family B IP4-4,6 substituted derivative compounds (e.g., Compounds 31 to 44).
  • Fig. 5 presents representative structures of Family C IP4-4,6 substituted derivative compounds (e.g., Compounds 45 to 49).
  • Fig. 6 presents representative structures of Family D IP4-4,6 substituted derivative compounds (e.g., Compounds 50 to 51).
  • Fig. 7 is a schematic representation of synthesis Scheme 1.
  • Fig. 8 is a schematic representation of synthesis Scheme 2.
  • Fig. 9 is a schematic representation of synthesis Scheme 3.
  • Fig. 10 is a schematic representation of synthesis Scheme 4.
  • Fig. 11 is a schematic representation of synthesis Scheme 5.
  • Fig. 12 represents the mean calcium content ( ⁇ SD) in Sham rats (no VitD3 treatment) and rats treated with vehicle or Compound 27 (5, 15, and 45 mg/kg) in (A) aorta, (B) heart, (C) femoral artery, (D) carotid arteries, and (E) kidney.
  • A aorta
  • B heart
  • C femoral artery
  • D carotid arteries
  • E kidney.
  • femoral and carotid arteries the mean of the calcium content in left and right vessels was used.
  • Statistical analysis One-way ANOVA with Fisher’s LSD test for post-hoc comparisons. (#) indicates significant differences vs.
  • Fig. 13 shows the mean normalized blood perfusion ( ⁇ SD) in Sham rats (no VitD3 treatment) and rats treated with vehicle, Compound 27 (5, 15, and 45 mg/kg) at D13.
  • Statistical analysis One-way ANOVA with Fisher’s LSD test for post-hoc comparisons. The result of the ANOVA was p ⁇ 0.0001.
  • (#) indicates significant differences vs sham,
  • (*) indicates significant differences vs vehicle,
  • ⁇ indicates significant differences vs Compound 27 5 mg/kg (only applies to other Compound 27 doses), p ⁇ 0.05.
  • N 10-12 animals/group.
  • Fig. 14 depicts the mean maximum walking distance ( ⁇ SD) in Sham rats (no VitD3 treatment) and rats treated with vehicle, Compound 27 (5, 15, and 45 mg/kg).
  • Statistical analysis One-way ANOVA with Fisher’s LSD test for post-hoc comparisons. The result of the ANOVA was p ⁇ 0.0001.
  • #) indicates significant differences vs. sham,
  • *) indicates significant differences vs vehicle,
  • ⁇ indicates significant differences vs Compound 27 5 mg/kg (only applies to other Compound 27 doses),
  • ⁇ indicates significant differences vs Compound 27 15 mg/kg (only applies to Compound 27 45 mg/kg),
  • J significant differences vs Compound 27 45 mg/kg, p ⁇ 0.05.
  • VIP6 aortic valve interstitial cells
  • Fig. 16 depicts an analysis of hypermineralization using Alizarin Red staining in 10 dpf zebrafish larvae.
  • Significant reduction of spinal hypermineralization (black boxes) in the larvae after treatment with Compound 27 was observed.
  • Quantification of calcified vertebral bodies in Compound 27-treated and untreated larvae through Image J analysis revealed a significance of p ⁇ 0.001, scale bar 500 pm.
  • the present invention refers to IP4-4,6 substituted derivative compounds of general formula I: a pharmaceutically acceptable salt thereof, or a combination thereof, for use in the treatment, inhibition of progression, and prevention of ectopic calcification and the consequences thereof.
  • n R1, R3, R7, and R11 are OPO3 2- or OPSO2 2 ’, and R5 and R9 are identical.
  • R5 and R9 are not identical.
  • the IP4-4,6 derivative is a sodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt.
  • the invention includes aspects in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention includes aspects 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.
  • Angina pectoris As used herein, the terms “angina pectoris” and “chronic stable angina” relate to chest pain or discomfort that occurs as the result of myocardial ischemia. It is a common presenting symptom among patients with coronary artery disease (CAD). Approximately 9.8 million Americans are estimated to experience angina annually, with 500,000 new cases of angina occurring every year.
  • CAD coronary artery disease
  • the term “approximately,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain aspects, the term “approximately” refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • Bolus administration As used herein, the terms “bolus administration” and “bolus injection” refer a fast intravenous injection lasting less than 10 seconds, or an intravenous infusion lasting less than 3 minutes.
  • Calcific aortic valve stenosis As used herein, the terms "calcific aortic valve stenosis” and “CAVS” refer to one of the most prevalent heart valve disorders in developed countries characterized by progressive fibro-calcific remodeling and thickening of the aortic valve leaflets. Over the years, this disease evolves to cause severe obstruction to cardiac outflow. In developed countries, CAVS is the third-most frequent cardiovascular disease after coronary artery disease and systemic arterial hypertension, with a prevalence of 0.4% in the general population and 1.7% in the population >65 years old (Lindman B, et al., Nat Rev Dis Primers. 2016; 2: 16006).
  • Calciphylaxis As used herein, the terms “calciphylaxis” and “CUA” refer to is a serious, uncommon disease in which calcium accumulates in small blood vessels of the fat and skin tissues. CUA causes blood clots, painful skin ulcers and may cause serious infections that can lead to death. CUA subjects usually suffer kidney failure and may require dialysis. The condition can also occur in people without kidney disease.
  • Cardiovascular disease in chronic kidney disease As used herein, the terms “cardiovascular disease in CKD patients” refer to the higher risk of CKD patients of developing cardiovascular diseases such as e.g., coronary artery disease, heart failure, arrhythmias, and sudden cardiac death.
  • Cardiovascular disease linked to aging refers to the fact that adults over 65 years of age have a high risk of cardiovascular diseases such as heart failure, coronary artery diseases, hypertension, cerebrovascular disease, peripheral arterial disease, valvular disease, and cardiac arrhytmias. Aging is associated with changes in the heart and blood vessels that increase a person's risk of developing cardiovascular disease (North B, et al., Circ Res. 2012; 110(8): 1097-1108). Age is an established independent risk factor for cardiovascular disease.
  • Compound As used herein, the term “compound,” is meant to include any and all free bases, isomers, and isotopes of the structure depicted. As used herein, the term “isomer” means any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer, or diastereomer of a compound. Compounds can include one or more chiral centers and/or double bonds and can thus exist as stereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • double-bond isomers i.e., geometric E/Z isomers
  • 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 of resolving them into their component enantiomers or stereoisomers are well- known.
  • a compound, salt, or complex of the present invention can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.
  • the term compound is used to refer to an IP4-4,6 substituted derivative of the present invention.
  • Consequences thereof refers to symptoms, sequelae, complications, and combinations thereof associated with the disease or condition.
  • symptom refers to subjective or physical sign, indication, or evidence of disease or physical disturbance observed by the subject. In general, the term refers to any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by a subject and indicative of disease. Symptoms are felt or noticed by the individual experiencing the symptom but may not easily be noticed by others. In some aspects, a symptom can be a mild symptom, a moderate symptom, or severe symptom.
  • the term “mild symptom” refers to a symptom that is not life threatening and does not require hospitalization or intensive care treatment (e.g., at a hospital ICU).
  • the term “moderate symptom” refers to a symptom that may become life threatening and may require hospitalization.
  • the term “severe symptom” refers to a symptom that is life threatening and requires intensive care treatment (e.g., at a hospital ICU).
  • the term “complication” refers to a pathological process or event occurring during a disease or condition that is not an essential part of the disease or condition; where it may result from the disease/condition or from independent causes.
  • complication refers to medical/clinical problems that are observed in subjects diagnosed with a disease or conditions disclosed herein.
  • a complication can be temporary.
  • a complication can be chronic or permanent.
  • the term "sequela" refers to a long term, chronic, or permanent complication.
  • Critical limb ischemia As used herein, the terms “critical limb ischemia” and “CLI” refer to a severe obstruction of the arteries which markedly reduces blood flow to the extremities and progresses to the point of severe pain and even skin ulcers, sores, or gangrene. Critical limb ischemia is a very severe condition of peripheral artery disease.
  • Ectopic calcification refers to an inappropriate biomineralization occurring in soft tissues. Ectopic calcifications are typically composed of calcium phosphate salts, including hydroxyapatite, but can also consist of calcium oxalates and octacalcium phosphate as seen in kidney stones.
  • Effective amount As used herein, the term "effective amount" of a therapeutic agent, in reference to (i) an IP4-4,6 substituted derivative of the present invention, (ii) any dosage form, pharmaceutical composition, or formulation disclosed herein comprising at least one IP4-4,6 substituted derivative of the present invention, or (iii) a combination of an IP4-4,6 substituted derivative of the present invention with one or more additional therapeutic agents), is that amount sufficient to effect beneficial or desired results.
  • the beneficial or desired results are, for example, clinical results, and, as such, an "effective amount” depends upon the context in which it is being applied.
  • the term “effective amount” can be used interchangeably with “effective dose,” “therapeutically effective amount,” or “therapeutically effective dose.”
  • an effective amount relates to the specific use of an IP4-4,6 substituted derivative.
  • an effective amount would be an amount of the IP4-4,6 substituted derivative capable of achieving the desired effect (e.g., the reduction of HAP crystallization/formation in blood serum or plasma).
  • Enteral administration refers to any administration of an IP4-4,6 substituted derivative of the present invention or a pharmaceutical composition comprising said derivative via the gastrointestinal tract.
  • Enteral administration includes, but is not limited to, the oral, sublingual, and rectal routes of administration.
  • General arterial calcification of infancy As used herein, the terms "general arterial calcification of infancy” and “GACI” relates to a disorder affecting the circulatory system that becomes apparent before birth or within the first few months of life, and which is characterized by abnormal calcification of the arteries and thickening of the arterial walls. These changes lead to stenosis and stiffness of the arteries, resulting in heart failure in some affected individuals, with signs and symptoms including difficulty breathing, edema, cyanosis, hypertension, and cardiomegaly.
  • IP4-4,6 substituted derivatives of the present invention refers to a compound of formula I:
  • R1, R3, R7, and R11 are OPO3 2- or OPSO2 2 ’, and R5 and R9 may or may not be identical, and wherein the R5 and R9 substituents are those disclosed in compound Families A, B, C, and D described in detail below, and salts thereof (e.g., pharmaceutically acceptable salts thereof).
  • the term IP4-4,6 substituted derivative of the present invention encompasses Compounds 1 to 53, any salt thereof (e.g., a sodium salt), and any combination thereof.
  • the term IP4-4,6 substituted derivative of the present invention encompasses a compound of formula I which is an intermediate in the synthesis of Compounds 1 to 53, e.g., a compound selected from the group consisting of the compounds listed in Table 1, any salt thereof (e.g., a sodium salt), and any combination thereof.
  • the term IP4-4,6 substituted derivative of the present invention encompasses a compound of formula I which is Compound 1 to Compound 53 and a compound selected from the group consisting of the compounds listed in Table 1, any salt thereof (e.g., a sodium salt), and any combination thereof.
  • Group consisting of Compound 1 to Compound 53 refers to a group of compounds that comprises Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, and 53.
  • the group consisting of Compound 1 to Compound 53 also comprises combinations thereof.
  • a combination of compounds from the group consisting of Compound 1 to Compound 53 can comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds from the group consisting of Compound 1 to Compound 53.
  • Group consisting of the compounds listed in Table 1 refers to a group of intermediate compounds used, e.g., for the synthesis of an IP4-4,6 substituted derivative of the present invention (e.g, a compound selected from the group consisting of Compound 1 to Compound 53) i.e., Intermediates II- 1 to 11-27, Intermediates III- 1 to III-47, Intermediates IV- 1 to IV-48, Intermediates VI'- 1 to IV-2, Intermediate V-l, Intermediate VI- 1, Intermediates VII- 1 to VII-2, Intermediates VIII- 1 to VIII-5, Intermediates IX-1 to IX-5, Intermediates X-l to X-3, Intermediates XI-1 to XI-2, Intermediates XII- 1 to XII-2 and Intermediates XIII- 1 to XIII-3.
  • the group consisting of the compounds listed in Table 1 also comprises combinations thereof.
  • a combination of compounds from the group consisting of the compounds listed in Table 1 can comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds from the group consisting of the compounds listed in Table 1.
  • Kidney failure-related diseases refers to disease processes of a widely diverse nature in individuals with kidney damage and can refer, but is not limited, to any disease related to calcium or calcium metabolism disorders, such as adynamic bone, bone cancer, bone mineral disease, calcific tendinitis, calcinosis cutis, calciphylaxis, renal lithiasis, cardiovascular calcification, cardiovascular disease, osteomalacia, osteoporosis, podagra, and rheumatoid arthritis.
  • adynamic bone, bone cancer, bone mineral disease, calcific tendinitis, calcinosis cutis, calciphylaxis, renal lithiasis, cardiovascular calcification, cardiovascular disease, osteomalacia, osteoporosis, podagra, and rheumatoid arthritis such as adynamic bone, bone cancer, bone mineral disease, calcific tendinitis, calcinosis cutis, calciphylaxis, renal lithiasis, cardiovascular calcification, cardiovascular disease
  • kidney failure-related diseases may be of the cardiovascular type including, but not limited to, aneurysm, angina pectoris, arteriosclerosis, atherosclerosis, cardiac disease, cardiovascular disease linked to aging, cerebrovascular disease, coronary disease, heart failure, hypertension, myocardial infarction, peripheral vascular disease, and thrombosis.
  • the patient with renal impairment may suffer concomitant cardiovascular accidents, events or diseases (e.g., ischemia, arrhythmia, myocardial infarction, stroke).
  • Non-bolus administration As used herein, the terms “non-bolus type” and “nonbolus administration” refer to an intravenous injection lasting 10 or more seconds, or an intravenous infusion lasting 3 or more minutes.
  • parenteral administration refers to the administration of an IP4-4,6 substituted derivative of the present invention characterized by the physical breaching of a tissue of a subject and the administration of the derivative through said breach in the tissue.
  • Parenteral administration includes, but is not limited to, the administration of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) or a pharmaceutical composition comprising the derivative, by the application of the derivative or the composition through, for instance, a surgical incision or through a tissue-penetrating non-surgical wound.
  • parenteral administration includes, but is not limited to, the epidural, intraarterial, intradermal, intrathecal, intramuscular, intraperitoneal, intrasternal injection, intravascular, intravenous, intravenous infusion, spinal, subcutaneous, and subcutaneous depot routes of administration.
  • Peripheral arterial disease As used herein, the terms “peripheral arterial disease” and “PAD” refer to a narrowing and/or stiffening of the peripheral arteries to the legs (most commonly), stomach, arms, and head. Symptoms include intermittent claudication (leg pain when walking which resolves with rest), skin ulcers, bluish skin, cold skin, or poor nail and hair growth.
  • Prevention refers to inhibiting the inception or decreasing the occurrence of a disease or condition in a subject (e.g., avert ectopic calcification or the consequence thereof in a subject.
  • Primary hyperoxaluria As used herein, the terms “primary hyperoxaluria” or “PH” refer to a disorder of glyoxylate metabolism characterized by an excess of oxalate resulting in kidney stones, nephrocalcinosis and ultimately renal failure and systemic oxalosis. There are 3 types of PH. Primary hyperoxaluria type 1 (PHI) is caused by a deficiency of the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine.
  • AKT glyoxylate-aminotransferase
  • glyoxylate When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs.
  • Primary hyperoxaluria type 2 (PH2), caused by mutations in the GRHPR gene, is an inherited disease in which the lack of a particular liver enzyme causes the body to accumulate excess amounts of oxalate.
  • Primary hyperoxaluria type 3 (PH3) is characterized by recurring calcium oxalate stones beginning in childhood or adolescence and, on occasion, nephrocalcinosis or reduced kidney function.
  • Pseudogout also known as “calcium pyrophosphate dihydrate (CPPD) crystal deposition disease” or “pyrophosphate arthropathy” refer to a rheumatologic disorder believed to be caused by calcium pyrophosphate crystal accumulation in connective tissues, particularly joints such as the knee joint.
  • CPPD calcium pyrophosphate dihydrate
  • pyrophosphate arthropathy refer to a rheumatologic disorder believed to be caused by calcium pyrophosphate crystal accumulation in connective tissues, particularly joints such as the knee joint.
  • Pseudoxanthoma elasticum As used herein, the terms “pseudoxanthoma elasticum” and “PXE” refer to a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic calcification that is most apparent in the elastic tissues of the skin, eyes, and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance.
  • any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • Subject By “subject” or “individual” or “animal” or “patient” or “mammal,” is meant 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, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; bears, food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters and guinea pigs; and so on.
  • the mam include, but
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • Therapeutic agent is used in a broad sense to include a composition comprising an IP4-4,6 substituted derivative of the present invention that can provide a significant therapeutic benefit to a subject in need thereof.
  • the subject in need thereof is a subject suffering or at risk of developing a disease or condition associated to pathological crystallization (e.g., a calcium phosphate or HAP crystallization).
  • a therapeutic agent according to the present invention can be an IP4-4,6 substituted derivative of the present invention, alone or in combination with one or more additional therapeutic agents, that is administered in an amount sufficient to effect beneficial or desired results.
  • therapeutic agent also encompasses prophylactic, diagnostic or imaging agents comprising an IP4-4,6 substituted derivative of the present invention, wherein the therapeutic agent is administered (i.e., topically, enterally or parenterally).
  • therapeutic agents of the present invention include agents that inhibit the formation or growth of calcium salts/crystals (e.g., calcium phosphates, HAP) and/or can ameliorate and/or prevent any symptom associated with pathological crystallization.
  • Topical administration refers to any administration of an IP4-4,6 substituted derivative of the present invention or a pharmaceutical composition comprising said derivative by applying the derivative or composition to a particular place on or in the body, such as the skin or a mucous membrane.
  • Topical administration includes, but is not limited to, the aural, cutaneous, nasal, transdermal, urethral, vaginal, and urethral routes of administration.
  • Treatment refers to the administration of compound or pharmaceutical composition of the present invention for (i) slowing, (ii) inhibiting the progression, (iii) stopping, or (iv) reverting the progression of a disease or condition after its clinical signs have appeared.
  • Control of the disease progression is understood to mean the beneficial or desired clinical results that include, but are not limited to, reduction of the symptoms, reduction of the duration of the disease, stabilization of pathological states (specifically to avoid additional deterioration), delaying the progression of the disease, improving the pathological state and remission (both partial and total).
  • the control of progression of the disease also involves an extension of survival compared with the expected survival if treatment was not applied.
  • the terms “treat” and “treatment” refer specifically to (a) stopping, reducing, inhibiting the progression or reverting the development of ectopic calcifications and the consequences therefor, (b) improving the mobility or walking ability (e.g., velocity, distance, endurance) in a subject administered with the compounds or pharmaceutical compositions of the present invention (c) reducing or improving the quality of life in a subject administered with the compounds or pharmaceutical compositions of the present invention.
  • ug, uM, uL As used herein, the terms “ug,” “uM,” and “uL” are used interchangeably with “ ⁇ g,” “ ⁇ M,” and “ ⁇ L” respectively.
  • the present invention discloses IP4-4,6 substituted derivatives, their methods of synthesis and their uses.
  • the IP4-4,6 substituted derivative is a compound of general formula I: wherein R1, R3, R7, and R11 independently represent OPO3 2- or OPSO2 2 ’, and R5 and R9 are substituent groups.
  • R5 and R9 are identical substituent groups.
  • R5 and R9 are not identical substituent groups.
  • the IP4-4,6 substituted derivative of the present invention is an acceptable salt (e.g., a pharmaceutically acceptable salt) or combination thereof of a compound of formula I.
  • an IP4- 4,6 derivative of the present invention can be, for example, a tetraionic salt (e.g., tetrasodium salt), a pentaionic salt (e.g., pentasodium salt), a hexaionic salt (e.g., hexasodium salt), a heptaionic salt (e.g., heptasodium salt), an octaionic salt (e.g., octasodium salt), a nonaionic salt (e.g., nonasodium salt) or a decaionic salt (e.g., decasodium salt).
  • a tetraionic salt e.g., tetrasodium salt
  • a pentaionic salt e.g., pentasodium salt
  • a hexaionic salt e.g., hexasodium salt
  • the presence of additional negatively charges group in a IP4-4,6 substituted derivatives can lead to the formation of complexes with additional ions.
  • the IP4-4,6 derivative of the present invention is a sodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt.
  • the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • Formula I and the rest of formulas presented in the invention are meant to encompass any isomers of the compounds covered thereby.
  • alkenyl or “alkenyl chain” in the context of the present invention refers to a linear or branched alkyl chain (e.g., containing between 2 and 10 carbon atoms) containing one or more double bonds, either substituted or non-substituted. Examples include, amongst others, ethenyl, 1 -propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2- butenyl, 3-butenyl, and 1,3-butadienyl.
  • alkyl or “alkyl chain” in the context of the present invention refers to a saturated hydrocarbon moiety, which can be linear, branched, cyclic or cyclic with linear or branched side chains.
  • alkyl includes partially unsaturated hydrocarbons such as propenyl. Examples are methyl, ethyl, propyl, isopropyl, n- or isobutyl, n- or cyclohexyl.
  • alkyl can extend to alkyl groups linked or bridged by hetero atoms. Hetero atoms in the context of the present invention are nitrogen (N), sulfur (S), oxygen (O), and halogen.
  • alkynyl or “alkynyl chain” in the context of the present invention refers to a linear or branched alkyl chain (e.g., containing between 2 and 10 carbon atoms) containing one or more triple bonds, either substituted or non-substituted. Examples include, amongst others, ethynyl, propynyl, 1-butynyl, and 3-butynyl.
  • An "amine function” or “amine group” is a function NRR’, with R and R’ selected independently, e.g., from hydrogen (-H) and an alkyl group such as an Ci-Cn alkyl, wherein n is and integer between 0 and 20.
  • a "hydroxy function" or "hydroxy group” is OH.
  • a "carboxylic acid function" or “carboxylic acid group” is COOH or its anion, COO".
  • a “carboxylic amide” is CONRR’ or NCOR, with R and R’ selected independently, e.g., from hydrogen (-H) and an alkyl group such as an Ci-Cn alkyl, wherein n is and integer between 0 and 20.
  • a "carbocycle” refers to a three- to 10-membered carbocyclic ring that can be saturated, partially unsaturated or aromatic (e.g., phenol, cyclopentane, cyclopropane) and which is bound to the rest of the molecule via any available C atom.
  • the term includes carbocyclic rings substituted with one or more heteroatoms (e.g., N, O, halogen atom).
  • a "heterocycle” refers to a three- to 10-membered cyclic ring containing at least one heteroatom selected from amongst N, O, and S, that can be saturated, partially unsaturated or aromatic (e.g., triazole, piperazine, pyrazole, thiophene) and which is bound to the rest of the molecule via any available C atom or N atom.
  • the term includes heterocycle rings substituted with one or more halogen atoms.
  • a "Cy” refers to a cyclic linker comprising a carbocycle or a heterocycle.
  • Examples of carbocycles and heterocycles include, amongst others, 1,3-phenyl, 1,4- 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, piperazyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzothiazolyl, cyclopropyl, cyclobutyl,
  • a "halogen” group refers to fluorine, chlorine, bromine or iodine.
  • OPO3 2- in the context of the present invention refers also indistinctly to OPO3H ’ and OPO3H2.
  • IP4-4,6 substituted derivatives of the present invention or intermediate compounds disclosed herein can be detected and/or quantified using the methods disclosed in US9612250. See also, US8377909, US8778912 and US20070066574.
  • IP4-4,6 substituted derivatives of the present invention can be present in any form commonly used in pharmaceutical technology. Particular aspects include, but are not limited to, the sodium salt, magnesium salt, potassium salt, ammonium salt, free acid, or a mixture of the preceding forms. Other pharmaceutically acceptable salts are known to the skilled artisan and can be obtained by methods previously described (Haynes M, et al., J. Pharmaceutical Sci. 2005; 94:2111-2120).
  • R1, R3, R7, and R11 independently represent phosphate (-OPO3 2- ) and R5/R9 corresponds to the formula -O-(alkyl)n-X (i.e., R5/R9 is an alkyl chain with or without ramification), wherein n is an integer between 1 and 20, wherein the terminal group X is selected from the group consisting of -H, -OR, -NRR', -COOR, -CONRR', - NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, -CF3, alkyl, alkenyl, alkynyl, carbocycle (saturated or unsaturated), and heterocycle (saturated or unsaturated), and wherein R and R' are H or an alkyl group.
  • R1, R3, R7, and R11 independently represent phosphate (-OPO3 2- ) and R5/R9 corresponds to the formula -O-(alkyl) y -Cy-(alkyl) y '-Z (i.e., R5/R9 comprises two alkyl chains connected by a cyclic linker interposed between the two alkyl chains), wherein each alkyl comprises y carbon (e.g., CH2) units, wherein y and y' are an integer between 0 and 10, wherein the distal alkyl chain comprises a terminal group Z selected from the group consisting of alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, - NHCOOR, -OCONR -NHSO2R, -NHCONRR', halogen, and -CF
  • R1, R3, R7, and R11 independently represent phosphate (-OPO3 2- ) and R5/R9 corresponds to the formula -O-(alkyl) y -A-(alkyl) y '-Z' (i.e., two alkyl chains connected by a linker A interposed between the two alkyl chains), wherein each alkyl chain comprises y carbon (e.g., CH2) units, wherein y and y' are an integer between 0 and 10, wherein the linker A is selected from the group consisting of -CONR-, -NHCOO-, - NHSO2-, -NHCONR-, -NHCO- and -OCONR-, wherein the distal alkyl chain comprises a terminal group Z' selected from the group consisting of -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R,
  • the IP4-4,6 substituted derivative of Family D is an analog of a compound from Family A, B or C in which at least one of R1, R3, R7 or R11 is thiophosphate (-OPSO2 2 ’). Throughout the present invention, this family of IP4-4,6 substituted derivatives is designated Family D.
  • one of R1, R3, R7 or R11 in a compound from Family A, B or C is thiophosphate (-OPSO2 2- ).
  • two of R1, R3, R7 or R11 in a compound from Family A, B or C are thiophosphate (-OPSO2 2- ).
  • three of R1, R3, R7 or R11 in a compound from Family A, B or C are thiophosphate (-OPSO2 2- ).
  • the IP4-4,6 substituted derivatives of Family D R1, R3, R7 or R11 in a compound from Family A, B or C are thiophosphate (-OPSO2 2- ).
  • the Family D compound contains thiophosphate (-OPSO2 2 ’) only at position R1.
  • the Family D compound contains thiophosphate (-OPSO2 2 ’) only at position R3.
  • the Family D compound contains thiophosphate (-OPSO2 2- ) only at position R7.
  • the Family D compound contains thiophosphate (-OPSO2 2- ) only at position R11. In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compound contains thiophosphate (-OPSO2 2- ) at positions R1, R3,R?, and R11. In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compound contains thiophosphate (-OPSO2 2- ) at positions R1 and R3. In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compound contains thiophosphate (- OPSO2 2 ’) at positions R1 and R7.
  • the Family D compound contains thiophosphate (-OPSO2 2- ) at positions R1 and R11. In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compound contains thiophosphate (-OPSO2 2- ) at positions R3 and R7. In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compound contains thiophosphate (-OPSO2 2- ) at positions R3 and R11. In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compound contains thiophosphate (- OPSO2 2 ’) at positions R7 and R11.
  • the Family D compound contains thiophosphate (-OPSO2 2- ) at positions R1, R3, and R7. In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compound contains thiophosphate (-OPSO2 2- ) at positions R1, R3, and R11. In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compound contains thiophosphate (-OPSO2 2- ) at positions R3, R7, and R11. In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compound contains thiophosphate (-OPSO2 2- ) at positions R1, R7, and R11.
  • an IP4-4,6 substituted derivative of the present invention comprises an IP4-4,6 substituted derivative from Family A, Family B, Family C, Family D or a combination thereof.
  • an IP4-4,6 substituted derivative of the present invention comprises an IP4-4,6 substituted derivative from Family A. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises an IP4-4,6 substituted derivative from Family B. In some, an IP4-4,6 substituted derivative of the present invention comprises an IP4-4,6 substituted derivative from Family C. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises an IP4-4,6 substituted derivative from Family D.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of an IP4-4,6 substituted derivative selected from the group consisting of Compounds 1 to 53 and combinations thereof. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of an IP4-4,6 substituted derivative selected from the group consisting of compounds 1 to 30 and combinations thereof. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of an IP4-4,6 substituted derivative selected from the group consisting of compounds 31 to 44 and combinations thereof. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of an IP4-4,6 substituted derivative selected from the group consisting of compounds 45 to 49 and combinations thereof.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of an IP4-4,6 substituted derivative selected from the group consisting of compounds 50 to 51 and combinations thereof.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 1.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 2.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 3.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 4.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 5.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 6. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 7. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 8. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 9. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 10. In some aspects, an IP4- 4,6 substituted derivative of the present invention comprises or consists of Compound 11. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 12.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 13. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 14. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 15. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 16. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 17. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 18. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 19.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 20. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 21. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 22. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 23. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 24. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 25. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 26.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 27. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 28. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 29. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 30. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 31. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 32. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 33.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 34. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 35. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 36. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 37. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 38. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 39. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 40.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 41. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 42. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 43. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 44. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 45. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 46. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 47.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 48. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 49. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 50. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 51. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 52. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 53.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 1 analog, wherein R1, R3, R7 or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 2 analog, wherein R1, R3, R7 or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4- 4,6 substituted derivative of the present invention comprises or consists of a Compound 3 analog, wherein R1, R3, R7 or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 4 analog, wherein R1, R3, R7 or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 5 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11 ; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 6 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 7 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 8 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4- 4,6 substituted derivative of the present invention comprises or consists of a Compound 9 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 10 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 11 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 12 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 13 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 14 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 15 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 16 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 17 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 18 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 19 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 20 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 21 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 22 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 23 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 24 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 25 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 26 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 27 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 28 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 29 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 30 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 31 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 32 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 33 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 34 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 35 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 36 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 37 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 38 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 39 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11 ; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 40 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 41 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 42 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 43 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 44 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 45 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 46 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 47 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2- ).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 48 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 49 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 50 analog, wherein R1, R3, R7, or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 51 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 52 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a Compound 53 analog, wherein R1, R3, R7, or R11 ; R1, R3, R7, and R11 ; R1 and R3; R1 and R7; R1 and R11 ; R3 and R7; R3 and R11 ; R7 and R11 ; R1, R3, and R7; R1, R3, and R11 ; R3, R7, and R11 ; or R1, R7, and R11 are thiophosphate (-OPSO2 2 ’).
  • the alkyl moiety in the R5 and R9 substituent groups of the IP4- 4,6 substituted derivative of the present invention includes at least one double or triple carbon bond, i.e., forming an alkenyl or alkynyl chain, respectively.
  • the alkenyl chains in the R5 and R9 substituent groups are identical.
  • the alkenyl chains in the R5 and R9 substituent groups are different.
  • the alkynyl chains in the R5 and R9 substituent groups are identical.
  • the alkynyl chains in the R5 and R9 substituent groups are different.
  • the alkyl moiety in the R5 and R9 substituent groups includes at least one double carbon bond and at least one triple carbon bond, forming a combination of an alkenyl and an alkynyl chain.
  • the combination of the alkenyl and the alkynyl chains in the R5 and R9 substituent groups is identical.
  • the combination of the alkenyl and the alkynyl chains in the R5 and R9 substituent groups is different.
  • the IP4- 4,6 substituted derivative of the invention including at least one double or triple carbon bond in the alkyl moiety of the R5 or R9 substituent groups is a Family A compound.
  • the Family A compound including at least one double or triple carbon bond is Compound 1 to Compound 30 and Compound 52.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula: wherein n is an integer between 1 and 20, alkyl is CH2 and X is -H. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, n is 5, alkyl is CH2 and X is -H (Compound 1). In some aspects, n is 10, alkyl is CH2 and X is -H (Compound 2).
  • n 14 alkyl is CH2 and X is -H (Compound 3). In some aspects, n is 3, alkyl is CH2 and X is -H (Compound 4). In some aspects, n is 7, alkyl is CH2 and X is -H (Compound 5).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula: wherein n is an integer between 1 and 20, alkyl is CH2 and X is selected from the group consisting of -OH and -OMe.
  • the IP4-4,6 derivative is a sodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, n is 5, alkyl is CH2 and X is -OH (Compound 6).
  • n 10
  • alkyl is CH2 and X is -OH (Compound 7).
  • n 14
  • alkyl is CH2 and X is -OH (Compound 8).
  • n 5
  • alkyl is CH2 and X is -OMe (Compound 9).
  • n 3
  • alkyl is CH2 and X is -OMe (Compound 10).
  • n 7, alkyl is CH2 and X is -OMe (Compound 11).
  • n is 9, alkyl is CH2 and X is -OMe (Compound 12).
  • n 19 alkyl is CH2 and X is -OMe (Compound 20).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula:
  • n is an integer between 1 and 20, alkyl is CH2 and X is an amine group. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt. In some aspects, n is 3, alkyl is CH2 and X is -NH2 (Compound 13). In some aspects, n is 5, alkyl is CH2 and X is -NH2 (Compound 14). In some aspects, n is 10 and X, alkyl is CH2 is -NH2 (Compound 15).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula:
  • n is an integer between 1 and 20, alkyl is CH2 and X is pyrazole or triazole. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, n is 5, alkyl is CH2 and X is pyrazol (Compound 16). In some aspects, n is 5, alkyl is CH2 and X is triazol (Compound 17).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula: wherein n is an integer between 1 and 20, alkyl is CH2 and X is -COOH. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt or decasodium salt. In some aspects, n is 5, alkyl is CH2 and X is -COOH (Compound 18). In some aspects, n is 10, alkyl is CH2 and X is -COOH (Compound 19). In some aspects, n is 3, alkyl is CH2 and X is -COOH (Compound 52).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula:
  • n is an integer between 1 and 20, alkyl is CH2 and X is -CONRR', -NHCOR, - NHCOOR, -NHCONRR' or -CF3. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, n is 3, alkyl is CH2 and X is -CF3 (Compound 22). In some aspects, n is 5, alkyl is CH2 and X is -CF3 (Compound 23).
  • n 3, alkyl is CH2 and X is -NHCOOMe (Compound 24). In some aspects, n is 5, alkyl is CH2 and X is -NHCOOMe (Compound 25). In some aspects, n is 3, alkyl is CH2 and X is -CONH2 (Compound 26). In some aspects, n is 5, alkyl is CH2 and X is -NHCOMe (Compound 27). In some aspects, n is 5, alkyl is CH2 and X is -NHCONHPr (Compound 30).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula: wherein n is an integer between 1 and 20, alkyl is CH2 and X is cyclopropane or cyclopentane. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, n is 2, alkyl is CH2 and X is cyclopropane (Compound 28). In some aspects, n is 2, alkyl is CH2 and X is cyclopentane (Compound 29).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula: wherein n is an integer between 1 and 20, alkyl is branched chain and X is -H. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 21 as shown in Fig. 3B.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula:
  • n is an integer between 1 and 20, alkyl is an alkynyl chain and X is -H. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, an IP4-4,6 substituted derivative of the present invention comprises or consists of Compound 53 as shown in Fig. 3B.
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula: wherein y and y' is an integer between 0 and 10, alkyl is CH2, Cy is selected from the group consisting of piperazine, triazole- 1, and triazole-2, and Z is selected from the group consisting of -COOH, -OMe, and -COCH3. See Fig. 4A.
  • the IP4-4,6 derivative is a sodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is an octasodium salt or nonasodium salt.
  • y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • y is 1, y' is 2, alkyl is CH2, Cy is triazole-2, and Z is -COOH (Compound 31).
  • y is 1, y' is 3, alkyl is CH2, Cy is triazole-2, and Z is -OMe (Compound 32).
  • y 1, y' is 6, alkyl is CH2, Cy is triazole-2, and Z is -OMe (Compound 33).
  • y is 2, y' is 0, alkyl is CH2, Cy is piperazine, and Z is -COCH3 (Compound 34).
  • y is 3, y' is 2, alkyl is CH2, Cy is triazole-1, and Z is -COOH (Compound 35).
  • y is 3, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is - OMe (Compound 36).
  • y is 4, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 37).
  • y is 5, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 38).
  • y is 6, y' is 1, alkyl is CH2, Cy is triazole- 1, and Z is -OMe (Compound 39). In some aspects, y is 6, y' is 0, alkyl is CH2, Cy is triazole-1, and Z is -COOH (Compound 40). In some aspects, y is 6, y' is 1/0, alkyl is CH2, Cy is triazole-1, and Z is -OMe/-COOH (Compound 41).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula: wherein y and y' is an integer between 0 and 10, alkyl is CH2, Cy is selected from the group consisting of 1,3-substituted phenyl and 1,4-substituted phenyl and Z is selected from the group consisting of -Me, -OMe, and -CF3. See Fig. 4B.
  • the IP4- 4,6 derivative is a sodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is an octasodium salt.
  • y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • y is 3, y' is 0, alkyl is CH2, Cy is 1,4-substituted phenyl, and Z is -Me (Compound 42).
  • y is 3, y' is 0, alkyl is CH2, Cy is 1,4-substituted phenyl, and Z is -OMe (Compound 43).
  • y is 3, y' is 0, alkyl is CH2, Cy is 1,3 -substituted phenyl, and Z is -CF3 (Compound 44).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula: wherein y and y' is an integer between 0 and 10, alkyl is CH2, A is selected from the group consisting of -NHCO and -NHCONH, and Z is selected from the group consisting of - COOH, phenyl, cyclopentyl, and thiophenyl.
  • the IP4-4,6 derivative is a sodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is an octasodium salt or decasodium salt.
  • y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • y is 3, y' is 3, alkyl is CH2, A is -NHCO, and Z is -COOH (Compound 45).
  • y is 3, y' is 0, alkyl is CH2, A is -NHCONH, and Z is phenyl (Compound 46).
  • y is 3, y' is 0, alkyl is CH2, A is -NHCONH, and Z is cyclopentyl (Compound 47).
  • y is 5, y' is 0, alkyl is CH2, A is -NHCO, and Z is phenyl (Compound 48). In some aspects, y is 5, y' is 0, alkyl is CH2, A is -NHCO, and Z is thiophenyl (Compound 49).
  • an IP4-4,6 substituted derivative of the present invention comprises or consists of a compound of the following formula: wherein n is an integer between 1 and 20, alkyl is CH2 and X is selected from the group consisting of -H and -OMe. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, n is 5, alkyl is CH2 and X is -H (Compound 50). In some aspects, n is 5, alkyl is CH2 and X is -OMe (Compound 51).
  • IP4-4,6 derivatives of the present invention are disclosed in myo form. However, the invention is also meant to encompass all the other isomers of the inositol scaffold, such as the scyllo, muco, ID-chiro, IL-chiro, neo, allo, epi, and cis counterparts of the IP4-4,6 derivatives of the invention.
  • the present invention also provides chemical intermediate compounds useful in the preparations of IP4-4,6 substituted derivative of the present invention (e.g., Compound 1 to Compound 53).
  • such intermediates are the compounds listed in Table 1.
  • An intermediate compound disclosed herein can be converted to an IP4- 4,6 substituted derivative of the present invention by utilizing the procedures described herein.
  • the present invention provides methods to produce an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53) comprising utilizing an intermediate compound selected from the group consisting of the compounds listed in Table 1.
  • the present invention also provides methods of producing the intermediate compounds disclosed herein.
  • the present invention provides methods of producing intermediates compounds selected from the group consisting of the compounds listed in Table 1 for producing IP4-4,6 substituted derivatives of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53).
  • IV-22 4,6-O-bis(5-(4-(Methoxymethyl)-lH-l,2,3-triazol-l-yl)pentyl)-l,2,3,5-O-tetrakis(3- oxido- 1 ,5 -dihydrobenzo [e] [ 1 , 3 ,2] dioxaphosphepin-3 -y l)-myo-inositol
  • IV-23 4,6-O-bis(6-(4-(Methoxymethyl)-lH-l,2,3-triazol-l-yl)hexyl)-l,2,3,5-O-tetrakis(3- oxido- 1 ,5 -dihydrobenzo [e] [ 1 , 3 ,2] dioxaphosphepin-3 -y l)-myo-inositol
  • IP4-4,6 substituted derivatives of the present invention and intermediates for their synthesis can be synthesized by using the methods described herein, as well as other processes known in the field of the organic chemistry.
  • the methods include, but are not limited to, the general procedures shown in the synthesis Schemes 1, 2, 3, and 4 described herein.
  • the present invention provides a method to manufacture an IP4-4,6 substituted derivative of the present invention comprising applying synthetic Scheme 1 disclosed below.
  • the present invention provides a method to manufacture an IP4-4,6 substituted derivative of the present invention comprising applying synthetic Scheme 2 disclosed below.
  • the present invention provides a method to manufacture an IP4-4,6 substituted derivative of the present invention comprising applying synthetic Scheme 3 disclosed below.
  • the present invention provides a method to manufacture an IP4- 4,6 substituted derivative of the present invention comprising applying synthetic Scheme 4 disclosed below.
  • the present invention provides a method to manufacture an intermediate for the synthesis of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) comprising applying synthetic Scheme 1 disclosed below.
  • the present invention provides a method to manufacture an intermediate for the synthesis of an IP4- 4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) comprising applying synthetic Scheme 2 disclosed below.
  • the present invention provides a method to manufacture an intermediate for the synthesis of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) comprising applying synthetic Scheme 3 disclosed below.
  • the present invention provides a method to manufacture an intermediate for the synthesis of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) comprising applying synthetic Scheme 4 disclosed below.
  • IP4-4,6 substituted derivatives of the present invention can be obtained, e.g., by deprotection of intermediates of formula IV (e.g., Intermediates IV-1 to IV-48) and intermediates of formula IV’ (e.g., Intermediates IV'- 1 to IV-2).
  • the "protective group” or PG can be, without limitation, benzyl, levulinylbenzyl, tert-butyl, o-xylenyl (e.g., by union of 2 PG in the same phosphate), 9- fluorenylmethyl, cyanethyl and other suitable protective groups in each case.
  • Intermediates of formula IV can be achieved, e.g., by phosphorylation of an intermediate of formula III according to procedures described in the literature, e.g., by a reaction with a phosphoroamidite derivative and subsequent oxidation with an oxidant (e.g., m-CPBA, H2O2, tBuOOH).
  • Intermediates of formula IV’ e.g., Intermediates IV'- 1 to IV'-2
  • intermediates of formula III e.g., Intermediates III- 1 to III-47
  • intermediates of formula II e.g., Intermediates II- 1 to 11-27
  • intermediates of formula II e.g., Intermediates II- 1 to 11-27
  • Preparation of (2) was previously described in the literature (Martin S, et al., J. Org. Chem. 1994; 59: 4805; Kardivel M, Org. & Biomolecular Chem. 2008; 6(11): 1966-72).
  • the "Leaving Group” or LG may be, without limitation, chloride, bromide, iodide, toluenesulfonyl (Ts) or methyl sulfonyl (Ms).
  • Scheme 2 As an alternative to Scheme 1, e.g., when R5 and R9 contain a substituted 1,2, 3 -triazole, compounds of formula I (i.e., the IP4-4,6 substituted derivatives of the present invention) can be obtained by following the alternative route described in Scheme 2 (Fig. 8).
  • intermediates of formula III e.g., Intermediates III-20, III-26, and III-27
  • intermediates VI e.g., Intermediates III-20, III-26, and III-27
  • an intermediate of formula VI e.g., Intermediate VI- 1
  • an alkyl agent e.g., an alkyl agent
  • Intermediates VI e.g., Intermediate VI-1
  • Scheme 3 As another alternative to Scheme 1 and Scheme 2, e.g., when R5 and R9 contain a substituted 1,2, 3 -triazole, compounds of formula I (i.e., the IP4-4,6 substituted derivatives of the present invention) can be obtained by an alternative route described in Scheme 3 (Fig. 9).
  • Intermediates of formula III e.g., Intermediates III-21 to III-25, III-42, and III-43
  • an Intermediate of formula IX e.g., Intermediates IX- 1 to 1X5
  • an alkynyl click agent e.g., a click reaction by using as starting materials an Intermediate of formula IX (e.g., Intermediates IX- 1 to 1X5) and an alkynyl click agent.
  • Intermediate IX can be achieved by alkylation and hydrolysis of Compound 2 with an azide alkylating agent.
  • R5 and R9 contain an amine group
  • compounds of formula I i.e., the IP4-4,6 substituted derivatives of the present invention
  • Scheme 3 Fig. 9
  • Intermediates IX e.g., Intermediates IX-1 to IX-5
  • Intermediates X e.g., Intermediates X-l to X3
  • Intermediates X can be deprotected to obtain compounds of formula I.
  • intermediates III e.g., Intermediates III-28, III-36 to III-41, and III-44 to III-46) can be achieved from intermediate VIII (e.g., Intermediates VIII- 1 to VIII-5) via an azide reduction (e.g., Intermediates XI- 1 to XI-2), subsequent deprotection (e.g., Intermediate XII- 1) and, finally, the formation of an amide/sulfonamide/urea or carbamate by reaction of the intermediate XII (e.g., Intermediate XII-1) with an appropriate reagent.
  • intermediate VIII e.g., Intermediates VIII- 1 to VIII-5
  • an azide reduction e.g., Intermediates XI- 1 to XI-2
  • subsequent deprotection e.g., Intermediate XII- 1
  • an amide/sulfonamide/urea or carbamate e.g., Intermediate XII-1
  • the order of the reaction can be changed, first obtaining an amide/sulfonamide/urea or carbamate from intermediate XIII (e.g., Intermediate XIII- 1 to XIII-3) and then, by hydrolysis, attaining intermediate III.
  • intermediate XIII e.g., Intermediate XIII- 1 to XIII-3
  • Any alkylating or click agent as well as reagents use for amide, sulfonamide, urea or carbamate formation can be commercially available or may be obtained following reactions well known in the field of organic chemistry.
  • methods include, but are not limited to, the general procedures shown in the Scheme 5 (Fig. 11).
  • IP4-4,6 substituted derivatives of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • a compound selected from the group consisting of Compound 1 to Compound 53 are presented herein and all of them are in the myo conformation.
  • any exemplary IP4-4,6 substituted derivative of the present invention in the myo conformation is not limited to the representative conformation displayed.
  • Compounds 1 to 53 and the intermediates presented herein would also encompass the corresponding equivalents in the scyllo, muco, ID-chiro, IL-chiro, neo, allo, epi, and cis conformations.
  • the myo-inositol isomer In its most stable conformation, the myo-inositol isomer assumes the chair conformation, which moves the maximum number of hydroxyls to the equatorial position, where they are farthest apart from each other. In this conformation, the natural myo isomer has a structure in which five of the six hydroxyls (the first, third, fourth, fifth, and sixth) are equatorial, whereas the second hydroxyl group is axial.
  • the present invention also provides methods to manufacture a medicament for the treatment of pathological crystallization comprising using an intermediate compound selected from the group consisting of the compounds listed in Table 1. Also provided is a compound of formula I (e.g., selected from the group consisting of Compound 1 to Compound 53) for use as a medicament. Also provided is the use of a compound of formula I (e.g., selected from the group consisting of Compound 1 to Compound 53) for the manufacture of a medicament for the prevention or treatment of a disease related to pathological crystallization.
  • a compound of formula I e.g., selected from the group consisting of Compound 1 to Compound 53
  • the present invention also provides pharmaceutical for use in the treatment, inhibition of progression, and prevention of (a) ectopic calcification or the consequences thereof and (b) a disease and/or condition related to ectopic calcification and the consequences thereof in a subject in need thereof, wherein the pharmaceutical composition comprises at least one IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53).
  • the pharmaceutical composition comprises an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) alone or together with one or more pharmaceutically acceptable excipients or carriers.
  • excipient refers to a substance which helps absorption of the elements of the pharmaceutical composition, stabilizes said elements, activates or helps preparation of the composition.
  • excipients used in parenteral formulations include, but are not limited to, antimicrobial agents (e.g., benzalkonium chloride, metacresol, thimerosal), co-solvents (e.g., ethanol), buffers, tonicity agents (e.g., NaCl) and pH adjusting factors (e.g., carbonate, citrate, phosphate solutions).
  • the "pharmaceutically acceptable vehicle” is a substance used in the composition to dilute any of the components contained therein to a determined volume or weight (e.g., a 0.9% (w/v) NaCl aqueous solution).
  • the pharmaceutically acceptable vehicle is an inert substance or a substance with an analogous action to any of the elements comprising the pharmaceutical composition of the present invention.
  • the role of said vehicle is to allow the incorporation of other elements, allow better dosing and administration or to provide consistency and shape to the composition.
  • compositions can comprise from approximately 1% to approximately 95% active ingredient.
  • the pharmaceutical compositions of the present invention can comprise from approximately 20% to approximately 90% active ingredient (i.e., an IP4-4,6 substituted derivative of the present invention or a combination thereof, alone or in combination, e.g., with one or more additional therapeutic agents).
  • Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient, e.g., an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline (e.g., a 0.9% (w/v) NaCl aqueous solution).
  • a pharmaceutically acceptable carrier such as sterile water or sterile isotonic saline (e.g., a 0.9% (w/v) NaCl aqueous solution).
  • Such formulations can be prepared, packaged, or sold in a form suitable for bolus administration or non-bolus administration.
  • Injectable formulations can be prepared, packaged, or sold in unit dosage form, such as in ampules 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 can further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
  • the active ingredient e.g., an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53)
  • a suitable vehicle e.g., sterile pyrogen-free water
  • 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 the known art, and may comprise, in addition to the active ingredient (e.g., an inositol phosphate of the present invention), additional ingredients such as the 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, for example.
  • Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
  • compositions for sustained release or implantation can comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
  • compositions and methods of making formulations for administering the IP4-4,6 substituted derivatives of the present invention, including controlled- or sustained-release formulations containing the said active agents, are described in the art.
  • Medicaments according to the invention are manufactured by methods known in the art, especially by conventional mixing, coating, granulating, dissolving or lyophilizing.
  • the present invention also provides a compound or a combination of compounds or pharmaceutical formulation according to any of the above aspects of the invention, in the broadest definition given, or as specified in any of the aspects presented above, for use as a medicament.
  • the present invention also provides a compound or combination of compounds or pharmaceutical formulation according to any of the above aspects of the invention, in the broadest definition given, or as specified in any of the aspects presented above, for use in the treatment and/or prevention of a disease or condition disclosed herein.
  • the present invention also provides a compound or combination of compounds or pharmaceutical formulation according to any of the above aspects of the invention, in the broadest definition given, or as specified in any of the aspects presented above, for the manufacture of a medicament for the prevention and/or treatment of a disease or condition disclosed herein.
  • the present invention also provides articles of manufacture and kits.
  • Such articles of manufacture and kits can comprise a container (e.g., a box) comprising one or more vials containing a formulation comprising (a) one or more of the IP4-4,6 substituted derivatives of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) (b) one or more pharmaceutical compositions of the invention and/or (c) solvents for their medical administration or other uses according to the methods disclosed herein.
  • kit or article of manufacture provided according to this invention can also comprise brochures or instructions describing the process of medical administration and dosages disclosed herein, or the use of the IP4-4,6 substituted derivatives of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) according to the methods disclosed herein.
  • kit or article of manufacture can comprise multiple vials, each one of them containing a single dose.
  • kit or article of manufacture can comprise one or more vials, each one of them comprising more than one dose.
  • the article of manufacture is a bag containing a solution of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53).
  • the article of manufacture is a bottle (e.g., a glass bottle or a plastic bottle) containing a solution of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53).
  • the article of manufacture is a bag containing an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) in powder form for reconstitution in an appropriate solvent.
  • the article of manufacture is a bottle (e.g., a glass bottle or a plastic bottle) containing an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) in powder form for reconstitution in an appropriate solvent.
  • an IP4-4,6 substituted derivative of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • kits and articles of manufacture can include instructions for carrying out one or more administrations of the IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) according to the methods and dosages disclosed herein.
  • administrations of the IP4-4,6 substituted derivative of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • kits and articles of manufacture can be affixed to packaging material or can be included as a package insert. While the instructions are typically written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term "instructions" can include the address of an internet site that provides the instructions.
  • the present invention refers to IP4-4,6 substituted derivative compounds of general formula I (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) for use in the treatment, inhibition of progression, and prevention of ectopic calcification or the consequences thereof in a subject in need thereof.
  • the present invention relates to a method for the treatment, inhibition of progression, and prevention of ectopic calcification or the consequences thereof in a subject in need thereof, which comprises administering a therapeutically effective amount of the IP4-4,6 substituted derivative compound of the invention.
  • the invention refers to the use of an IP4-4,6 substituted derivative compound of the invention for the manufacture of a medicament for the treatment, inhibition of progression, and prevention of ectopic calcification or the consequences thereof in a subject in need thereof.
  • the IP4-4,6 substituted derivative is a compound of general formulas II to XIV or any combination thereof.
  • the IP4-4,6 substituted derivative is Compound 1, Compound 3, Compound 6, Compound 27 or any combination thereof.
  • a therapeutically effective amount of the IP4-4,6 substituted derivative of the invention is administered to the subject in need thereof.
  • the IP4-4,6 substituted derivatives of the present invention can be administered by the topical, enteral or parenteral route of administrations.
  • the parenteral administration is via the intravenous, intraperitoneal, intramuscular, intraarterial or subcutaneous route of administration.
  • the compound can be administered as a component of a hemodialysis, hemofiltration or peritoneal dialysis solution.
  • the IP4-4,6 substituted derivative of the present invention can be administered by any appropriate method, e.g., a method that provokes a non-bolus type release or effect, such as intravascular (e.g., intravenous) infusion, other parenteral (e.g., subcutaneous, subcutaneous depot, intraperitoneal, intramuscular, intradermal, intrathecal, epidural, spinal or others known to a person skilled in the art), topical (e.g., intranasal, inhalation, intravaginal, transdermal or others known to a person skilled in the art), enteral (e.g.. oral, sublingual, rectal.) administrations, oral, spinal, intraperitoneal preparations or others known to a person skilled in the art.
  • intravascular e.g., intravenous
  • other parenteral e.g., subcutaneous, subcutaneous depot, intraperitoneal, intramuscular, intradermal, intrathecal, epidural, spinal or others known to a person skilled
  • an appropriate method of administration consists of an administration (e.g, a non-bolus type) of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) via a dialysis apparatus (before or after the filter) instead of directly injecting the IP4-4,6 substituted derivative of the present invention into the patient intravenously.
  • an administration e.g, a non-bolus type
  • an IP4-4,6 substituted derivative of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • a dialysis apparatus before or after the filter
  • IP4-4,6 substituted derivative of the present invention can be treated with the IP4-4,6 substituted derivative of the present invention as it leaves the patient and circulates through the dialysis circuit and, when the blood containing the IP4-4,6 substituted derivative of the present invention returns to the body, the IP4-4,6 substituted derivative has been introduced into the blood in a manner that presents a series of advantages.
  • administration of an IP4-4,6 substituted derivative of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • the dialysis apparatus allows the blood to equilibrate with the dialysis fluid prior to returning to the body.
  • an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) is administered intravenously via intravenous infusion.
  • an IP4-4,6 substituted derivative of the present invention is administered subcutaneously.
  • an IP4-4,6 substituted derivative of the present invention is administered topically.
  • when an IP4-4,6 substituted derivative of the present invention is administered to a patient undergoing dialysis such administration (e.g., intravenous administration via infusion) can occur during a dialysis treatment.
  • the IP4-4,6 substituted derivative of the present invention is administered before a dialysis treatment.
  • the IP4-4,6 substituted derivative of the present invention is administered after a dialysis treatment.
  • the present invention refers also to a pharmaceutical composition for use in the treatment, inhibition of progression, and prevention of ectopic calcification or the consequences thereof in a subject in need thereof comprising an IP4-4,6 substituted derivative of the present invention or any combination thereof, and at least one pharmaceutically acceptable excipient.
  • the IP4-4,6 substituted derivative is a compound of general formulas II to XIV or any combination thereof.
  • the IP4-4,6 substituted derivative is Compound 1, Compound 3, Compound 6, Compound 27 or any combination thereof.
  • a therapeutically effective amount of the pharmaceutical composition of the invention is administered to the subject in need thereof.
  • the present invention also provides methods to manufacture a medicament for the treatment, inhibition of progression, and prevention of ectopic calcification or the consequences thereof which comprises using an intermediate compound selected from the group consisting of the compounds listed in Table 1.
  • Ectopic calcifications are related to the pathological crystallization of calcium and arise as complications in numerous diseases and conditions. Ectopic calcifications are often damaging in soft tissues such as aorta, brain, carotid, femoral, heart, heart valves, joints, kidney, and lungs. This is often taken for granted as an age-dependent process, but recent data suggest that a myriad of molecules might modulate this process in an active fashion (Nitschke Y, et al., Trends Cardiovasc Med. 2012; 22(6): 145-149).
  • the IP4-4,6 substituted derivatives of the present invention are selective calcification inhibitors that work by binding to the growth sites of hydroxyapatite (HAP) crystals, thereby selectively inhibiting the final common step in the pathway of ectopic calcification, including vascular calcification. Since the IP4-4,6 substituted derivatives of the present invention are effective in inhibiting vascular calcification in various types of soft tissue, they could be useful for treating diseases and/or conditions associated to the ectopic calcification of such specific types of soft tissue.
  • HAP hydroxyapatite
  • the present invention refers to a IP4-4,6 substituted derivatives compound or pharmaceutical composition of the invention for use in the treatment, inhibition of progression, and prevention of a disease and/or condition related to ectopic calcification or the consequences thereof in a subject in need thereof.
  • the disease and/or condition related to ectopic calcification or the consequences thereof according to the invention include, but are not limited to, adrenal and intracranial calcification in familial cerebral cavernous malformations, adynamic bone, age-related macular degeneration (AMD) related to calcium deposits, bone cancer, bone mineral disease, breast calcification, calcific band keratopathy, calcific tendinitis, calcification in osteoarthritis, calcification of articular cartilage in osteoarthritis, calcification of joints and arteries (CALJA), calcification of the seminal vesicles, calcinosis cutis, calciphylaxis (CUA), calcium pyrophosphate deposition disease (CPPD), cardiovascular diseases and/or associated conditions, chondrocalcinosis, colon cancer, diabetic kidney disease, dystrophic calcification, failure of renal transplant grafts, familial cerebral cavernous malformations (FCCM), fibrodysplasia ossificans
  • the cardiovascular diseases and/or associated conditions related to ectopic calcification or the consequences thereof according to the invention include, but are not limited to acute ischemic stroke (ACS), aneurysm, angina pectoris (chronic stable angina), aortic artery calcification, aortic calcification, aortic stenosis, aortic valve calcification, arrhythmia, arteriosclerosis, arterial stiffness, arteriovenous fistula (AVF) failure, atherosclerosis, calcific aortic valve stenosis (CAVS), cardiac death, cardiac disease, cardiovascular calcification, cardiovascular disease in chronic kidney disease (CKD) patients, cardiovascular disease linked to aging, cardiovascular mortality, cerebrovascular disease, congestive heart failure, coral reef aorta (CRA), coronary artery calcification, coronary artery disease, coronary disease, critical limb ischemia (CLI), electrocardiographic abnormalities, general arterial calcification of infancy (GACI), heart failure
  • ACS acute
  • the present invention refers to IP4-4,6 substituted derivative compounds of general formula I (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) or the pharmaceutical compositions of the invention for use in the treatment, inhibition of progression, and prevention of ectopic calcification or the consequences thereof in a subject in need thereof, wherein the ectopic calcification occurs or may occur in aorta, brain, carotid, femoral, heart, heart valve, joint, kidney or lung tissue or any combination thereof.
  • general formula I e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • pharmaceutical compositions of the invention for use in the treatment, inhibition of progression, and prevention of ectopic calcification or the consequences thereof in a subject in need thereof, wherein the ectopic calcification occurs or may occur in aorta, brain, carotid, femoral, heart, heart valve, joint, kidney or lung tissue or any combination thereof.
  • diseases and/or conditions related to ectopic calcification or the consequences thereof in aorta tissue include, but are not limited to, aortic artery calcification, aortic calcification, aortic stenosis, aortic valve calcification, arteriosclerosis, arterial stiffness, atherosclerosis, calcific aortic valve stenosis (CAVS), cardiovascular disease linked to aging, cardiovascular mortality, coral reef aorta (CRA), electrocardiographic abnormalities, general arterial calcification of infancy (GACI), heart failure, peripheral arterial disease (PAD), and peripheral vascular disease (PVD).
  • diseases and/or conditions related to ectopic calcification or the consequences thereof in brain tissue include, but are not limited to, adrenal and intracranial calcification in familial cerebral cavernous malformations, cerebrovascular disease, familial cerebral cavernous malformations (FCCM), idiopathic brain calcification (Fahr's disease), pineal calcification, and primary familial brain calcification (PFBC).
  • diseases and/or conditions related to ectopic calcification or the consequences thereof in carotid tissue include, but are not limited to ischemia, peripheral arterial disease (PAD), peripheral vascular disease (PVD), stroke, and thrombosis.
  • diseases and/or conditions related to ectopic calcification or the consequences thereof in femoral tissue include, but are not limited to, arteriosclerosis, arterial stiffness, atherosclerosis, cardiovascular calcification, cardiovascular disease in chronic kidney disease (CKD) patients, cardiovascular disease linked to aging, cardiovascular mortality, critical limb ischemia (CLI), general arterial calcification of infancy (GACI), ischemia, peripheral arterial disease (PAD), peripheral vascular disease (PVD), thrombosis, and vascular calcification.
  • CLI critical limb ischemia
  • GACI general arterial calcification of infancy
  • PAD peripheral arterial disease
  • PVD peripheral vascular disease
  • thrombosis thrombosis
  • diseases and/or conditions related to ectopic calcification or the consequences thereof in heart and heart valve tissues include, but are not limited to, aneurysm, angina pectoris (chronic stable angina), aortic valve calcification, arrhythmia, arteriosclerosis, arterial stiffness, atherosclerosis, calcific aortic valve stenosis (CAVS), cardiac death, cardiac disease, cardiovascular calcification, cardiovascular disease in chronic kidney disease (CKD) patients, cardiovascular disease linked to aging, cardiovascular mortality, cerebrovascular disease, congestive heart failure, coronary artery calcification, coronary artery disease, coronary disease, electrocardiographic abnormalities, general arterial calcification of infancy (GACI), heart failure, hypertension, ischemia, left ventricular hypertrophy, myocardial infarction, and myocardial ischemia.
  • GCI general arterial calcification of infancy
  • diseases and/or conditions related to ectopic calcification or the consequences thereof in joint tissue include, but are not limited to, calcific tendinitis, calcification in osteoarthritis, calcification of articular cartilage in osteoarthritis, calcification of joints and arteries (CALJA), dystrophic calcification, ad pseudogout.
  • diseases and/or conditions related to ectopic calcification or the consequences thereof in kidney tissue include, but are not limited to, failure of renal transplant grafts, kidney stones (i.e., renal lithiasis), nephrocalcinosis, and primary hyperoxaluria (PH).
  • diseases and/or conditions related to ectopic calcification or the consequences thereof in lung tissue include, but are not limited to, dystrophic calcification, and metastatic calcification.
  • diseases and/or conditions related to ectopic calcification or the consequences thereof in skin tissue include, but are not limited to, calciphylaxis (CUA) and pseudoxanthoma elasticum (PXE).
  • the IP4-4,6 substituted derivative is a compound of general formulas II to XIV or any combination thereof.
  • the IP4-4,6 substituted derivative is Compound 1, Compound 3, Compound 6, Compound 27 or any combination thereof.
  • the administration of the IP4-4,6 substituted derivatives of the present invention to subject inhibits the formation and/or growth of hydroxyapatite (HAP) crystals and their deposition in ectopic calcifications.
  • HAP hydroxyapatite
  • This mechanism of action could mediate the therapy of many diseases and/conditions related to ectopic calcification and the consequences therefor.
  • the IP4-4,6 substituted derivatives of the present invention may also be effective in reducing the risk of cardiovascular events in patients.
  • the IP4-4,6 substituted derivatives of the present invention By inhibiting HAP formation, the IP4-4,6 substituted derivatives of the present invention would slow down the progression of coronary artery calcification (CAC). Since CAC is associated with increased cardiovascular mortality, a reduction in its rate of progression may reduce the risk of cardiovascular events. Moreover, the IP4-4,6 substituted derivatives of the present invention may additionally slow down the calcification of aortic valve leaflets, in view of their inhibitory properties over HAP formation.
  • Pseudoxanthoma elasticum (PXE) is characterized by ectopic mineralization and fragmentation of elastic fibers in the skin, eye, vascular, and gastrointestinal system. As the IP4-4,6 substituted derivatives of the present invention inhibit HAP formation, the eyesight of PXE patients, for example, could be stabilized or improved.
  • the present invention refers to IP4-4,6 substituted derivative compounds of general formula I (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) or the pharmaceutical compositions of the invention for use in the treatment, inhibition of progression, and prevention of a disease and/or condition related to ectopic calcification or the consequences thereof in a subject in need thereof, wherein (i) a therapeutically effective amount of the IP4-4,6 substituted derivative or pharmaceutical composition of the invention is administered to the subject and (ii) the disease and/or condition is selected from the group consisting of angina pectoris (chronic stable angina), calcific aortic valve stenosis, calciphylaxis, cardiovascular disease in CKD patients, peripheral arterial disease, critical limb ischemia, general arterial calcification of infancy, pseudogout, primary hyperoxaluria, and pseudoxanthoma elasticum.
  • the IP4-4,6 substituted derivative is a compound of general formulas II
  • the present invention relates to a method for the treatment, inhibition of progression, and prevention of ectopic calcification or the consequences thereof in a subject in need thereof, which comprises administering a therapeutically effective amount of the IP4-4,6 substituted derivative or pharmaceutical composition of the invention.
  • an IP4-4,6 substituted derivatives of formulas II and VII, or any combination thereof is administered to the subject.
  • Compound 1, Compound 3, Compound 6, and Compound 27 or any combination thereof, is administered to the subject.
  • the consequence of the ectopic calcification is, e.g., (i) a functional complication, (ii) pain, (iii) a trophic complication, (iv) an infection, or (v) a combination thereof.
  • the function complication is, e.g., a limitation of range of motion and/or joint function.
  • the trophic complication is, e.g., ischemia and/or a lesion.
  • the lesion is, e.g., necrosis of the cutaneous and/or subcutaneous tissues.
  • administration of the dosage of IP4-4,6 substituted derivative or pharmaceutical composition of the present invention to a subject in need thereof causes a reduction in lesions, e.g., as determined by the Bates-Jensen Wound Assessment tool or other methods known in the art (Bates-Jensen B, Decubitus 1992; 5(6):20-28).
  • the reduction in lesions comprises, e.g., a reduction in the severity of the lesions, a reduction in the size of the lesions, and reduction in the duration of the lesions, or a combination thereof.
  • administration of the dosage of IP4-4,6 substituted derivative or pharmaceutical composition of the present invention to the subject causes an improvement in lesion healing.
  • the administration of the IP4-4,6 substituted derivative or pharmaceutical composition of the present invention to the subject causes a reduction in pain.
  • the subject has renal failure.
  • the subject is on hemodialysis.
  • subject is human.
  • IP4-4,6 substituted derivative or pharmaceutical composition of the present invention to a subject in need thereof an improvement on global wound quality of life (QoL) as determined by using a validated wound-associated QoL questionnaire or other methods known in the art (Marchin M, et al., Int Wound J. 2017; 14(6): 1299-1304).
  • QoL global wound quality of life
  • the subject has renal failure.
  • the subject is on hemodialysis.
  • subject is human.
  • Kidney failure also known as renal impairment or kidney disease, is a disease that causes a progressive loss of kidney function, with a concomitant decrease in the glomerular filtration rate (GFR) or index. Renal impairment, together with treatment of the disease, leads to hypercalcemia and hyperphosphatemia. Hypercalcemia and hyperphosphatemia may cause cardiovascular calcification, although a deficiency of repressor factors (e.g., matrix Gia protein, osteopontin, fetuin, or vitamin K) or an imbalance in promoting factors (e.g., vitamin D, FGF23, inflammatory cytokines, lipid deposits, apoptotic bodies, nucleational complexes) may delay or accelerate the process.
  • CKD-MBD chronic kidney disease-mineral bone disease
  • the IP4-4,6 substituted derivatives and pharmaceutical compositions of the present invention can be used for treating, inhibiting the progression, and preventing some of the diseases and/or conditions related to ectopic calcification or the consequences thereof, as listed above, in patients with kidney failure.
  • the disease and/or condition related to ectopic calcification or the consequences thereof is a kidney failure-related disease.
  • the patient with kidney failure is on dialysis.
  • the IP4-4,6 substituted derivatives and pharmaceutical compositions of the invention are administered to the patient with kidney failure via intravenous infusion. In some aspects the intravenous infusion is performed using a dialysis apparatus.
  • the IP4-4,6 substituted derivative is a compound of general formulas II to XIV or any combination thereof. In some aspects, the IP4-4,6 substituted derivative is Compound 1, Compound 3, Compound 6, Compound 27 or any combination thereof. In some aspects, a therapeutically effective amount of the IP4-4,6 substituted derivative of the invention is administered to the patient with kidney failure.
  • the IP4-4,6 substituted derivatives of the present invention can be used in dialysis liquids, e.g., during hemodialysis. Accordingly, the present invention also provides dialysis liquids, e.g., hemodialysis liquids comprising an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), a pharmaceutically acceptable salt thereof, or any combination thereof, wherein the administration of the IP4-4,6 substituted derivative, pharmaceutically acceptable salt thereof, or combination thereof to the subject in need thereof is effective in treating, inhibiting the progression, and preventing (i) ectopic calcification and the consequences thereof or (ii) a disease and/or condition related to ectopic calcification or the consequences thereof.
  • an IP4-4,6 substituted derivative of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • a pharmaceutically acceptable salt thereof e.g., a compound selected
  • Step 1 9-Methoxynonan-l-ol (3): A mixture of 9-bromononan-l-ol (0.5 g, 2.24 mmol) and sodium methoxide 4N (25 mL, 100 mmol)) was stirred for 18 h at 40°C. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 4: 1) to afford 324 mg of (3) (83% yield).
  • Step 2 9-Methoxynonyl 4-methylbenzenesulfonate (7): To a solution of (3) (1.5 g, 8.61 mmol) in dichloromethane (DCM, 28.7 mL) triethylamine (TEA (1.80 mL, 12.91 mmol) and tosyl chloride (Ts-Cl, 2.13 g, 11.19 mmol) were added. The reaction mixture was stirred for 24 h at rt then quenched with water and washed with brine. The organic layer was dried over with Na2SOr, filtered and concentrated in vacuum.
  • DCM dichloromethane
  • Ts-Cl triethylamine
  • Ts-Cl tosyl chloride
  • Step 1 5-Azidopentyl 4-methylbenzenesulfonate (10)
  • Step 1 5-Azidopentan-l-ol (9): A solution of 5 -bromopentan- l-ol (0.10 mL, 0.89 mmol) and sodium azide (63 mg, 0.98 mmol) in dimethylformamide (DMF, 0.2 M) was stirred for 18 h at 80°C. Then, the reaction mixture was quenched with water/EtOAc and was washed with brine (3x). The organic layer was dried over with Na2SOr, filtered, and concentrated in vacuum to afford 57 mg of (9) (50%).
  • Step 1 10-Azidodecan-l-ol (11): A solution of 10-bromodecan-l-ol (0.42 mL, 2.11 mmol) and sodium azide (151 mg, 2.32 mmol) in DMF (0.2 M) was stirred for 18 h at 80°C. Then, reaction mixture was quenched with water/EtOAc and washed with brine (3x). The organic layer was dried over with Na2SOr, filtered and concentrated in vacuum to afford 388 mg of (11) (92%).
  • Step 2 10-Azidodecyl 4-methylbenzenesulfonate (12): To a solution of (11) (388 mg, 1.95 mmol) in DCM (0.2M) at 0°C, TEA (407 pL, 2.92 mmol) and Ts-Cl (371 mg,
  • Step l 6-Azidohexan-l-ol (16): A solution of 6-bromohexan-l-ol (428 pL, 3.27 mmol) and sodium azide (850 mg, 13.08 mmol) in DMF (0.8 M) was stirred for 18 h at 80°C. Then, the reaction mixture was quenched with water/EtOAc, and washed with brine (3x). The organic layer was dried over with Na2SOr, filtered, and concentrated in vacuum to afford 470 mg of (16) (>99%).
  • Step 2 6-Azidohexyl 4-methylbenzenesulfonate (17): At 0°C, p-Ts-Cl (720 mg, 3.78 mmol) was added to a solution of (16) (515 mg, 3.60 mmol) and TEA (1.5 mL, 10.79 mmol) in dry DCM (0.6 M). The reaction mixture was stirred overnight at rt. It was diluted with EtOAc and washed with 10% aqueous solution of NaHSOr. The aqueous phase was extracted with EtOAc (3x). The combined layers were washed with saturated aqueous solution of NaHCOs and dried over anhydrous Na2SO4.
  • Step 1 4-Azidobutan-l-ol (18): A solution of 4-bromobutan-l-ol (298 pL, 3.27 mmol) and sodium azide (850 mg, 13.08 mmol) in DMF (0.8 M) was stirred for 18 h at 80°C. Then, reaction mixture was quenched with water/EtOAc and was washed with Brine (3x). The organic layer was dried over with Na2SOr, filtered, and concentrated in vacuo to afford 213 mg of (18) (56%).
  • Step 2 4-Azidobutyl 4-methylbenzenesulfonate (19): At 0°C, Ts-Cl (370 mg, 1.94 mmol) was added to a solution of (18) (213 mg, 1.85 mmol) and TEA (774 pL, 5.55 mmol) in dry DCM (0.6 M). The reaction mixture was stirred overnight at rt. It was diluted with EtOAc and washed with 10% aqueous solution of NaHCCh. The aqueous phase was extracted with EtOAc (3x). The combined layers were dried over with anhydrous Na2SO4.
  • Step 1 2-((9-Bromononyl)oxy)tetrahydro-2H-pyran (26): To a solution of 9- bromononan-l-ol (6.17 g, 27.6 mmol) and 2,3-dihydro-2H-pyran (3.78 mL, 23 mmol), p- TSA, (105 mg, 0.55 mmol) were added. The mixture was stirred for 18 hours at rt. The mixture was diluted with Na2CCh IN, extracted with ethyl ether (2x), dried over with Na2SO4, filtered, and the solvents removed in vacuo.
  • Step 3 10-Methoxydec-l-yne (28): To a stirred solution of sodium methoxide 5M in MeOH, (27) (4.45 g, 19.1 mmol) was added and left stirring at 45°C for 18h. Then, the suspension was dissolved in water and extracted with Et2O (2x). The organic layer was dried over with Na2S0r and evaporated to dryness. The crude product was purified by column chromatography (5% EtOAc in Hex) to give (28) (2.58 g, 80%).
  • Step 4 2-((19-Methoxynonadec-10-yn-l-yl)oxy)tetrahydro-2H-pyran (29): To a solution of (28) (4 g, 23.8 mmol) in 30 mL of THF and 25 mL of HMPA cooled at -40°C, rz-BuLi (15.5 mL, 24.8 mmol) was slowly added, followed by stirring at the same temperature for 30 minutes, and further stirring at 0°C for 30 minutes. After cooling to - 20°C, a solution of (26) (6.09 g, 19.81 mmol) in 25 mL of HMPA was slowly added. After stirring at the same temperature for 10 minutes, the temperature was increased to rt.
  • Step 5 19-Methoxynonadec-10-yn-l-ol (30): To a solution of (29) (2.36 g, 6 mmol) in MeOH (10 mL), p-TSA (68 mg, 0.36 mmol) was added portionwise. The resulting solution was stirred at 60°C for 16 h and then concentrated in vacuo. The residue was dissolved in sat. aq. NaHCO3 and extracted with tBuMeO (2x). The combined organic extracts were washed with brine solution and dried with Na2SO4. No further purification was necessary, yielding 1.32 g (71%) of (30).
  • Step 6 19-Methoxynonadec-10-yn-l-yl 4-methylbenzenesulfonate (31): To a solution of (30) (1.32 g, 4.25 mmol) in THF (8.5 mL), Ts-Cl (973 mg, 5.10 mmol) and NaOH 5M (1.020 mL, 5.10 mmol) were added and the obtained mixture was stirred for 18 h. Water was added to the reaction mixture and extracted with tBuMeO (2x). The combined organic layer was washed with water, brine, dried over with Na2S0r, and concentrated in vacuo.
  • Benzyl (2,5-dioxopyrrolidin-l-yl) glutarate (32) To a solution of 5- (benzyloxy)-5-oxopentanoic acid (285 mg, 1.28 mmol) and (2,5-dioxopyrrolidin-l-yl) carbonate (600 mg, 2.34 mmol) in DCM (0.05 M), TEA (357 pL, 2.56 mmol) was added. The reaction mixture was stirred for 24 h at rt, then quenched with water, and washed with brine. The organic layer was dried over with Na2S0r, filtered and concentrated in vacuum.
  • Procedure B To a solution of (2) (1 eq) in DMF (0.2 M) at 0°C, LiH was added. When the addition was complete, the mixture was stirred for 5 minutes at rt. Finally, the alkylating agent was added. The reaction was allowed to stir during different times and temperatures depending on the alkylating agent, then quenched with water, and extracted with EtOAc. The organic layer was dried over with Na2S0r, filtered, and concentrated in vacuum. The residue was purified by flash chromatography (silica gel) to afford pure compounds.
  • Procedure K To a suspension of Intermediate (VI) (1 eq) and Cui (0.03 eq) in DCM (0.1 M), a solution of azide reagent (2 eq), DIPEA (0.07 eq) and AcOH (0.07 eq) in DCM/MeOH (IM) was added. The reaction mixture was stirred at 35°C for 20 h under inert atmosphere and concentrated in vacuum to afford the desired compound.
  • Procedure I Phosphorylated compound (IV) or (X) was dissolved in a mixture of THF/MeOH/water (3: 1 : 1, 0.01 M) followed by addition of excess palladium hydroxide on carbon. The mixture was placed under hydrogen atmosphere and stirred 2 days at rt. The mixture was then purged with nitrogen, filtered, and concentrated. The compound was brought at pH 9-10 by addition of dilute aqueous NaOH (1 N), and the residue was purified in a sephadex column (PD-10, G-25-M) by eluting with water. All fractions were lyophilized and analyzed by 1 H-RMN.
  • fractions containing product were purified further in a reverse phase cartridge (Sep-Pack® C 18 cartridge, 1 g, Waters Corp., Milford, MA, USA) by eluting with water. All fractions were lyophilized and analyzed by 1 H- RMN.
  • a reverse phase cartridge Sep-Pack® C 18 cartridge, 1 g, Waters Corp., Milford, MA, USA
  • Procedure J Phosphorylated compound (IV) or (X) was dissolved in a mixture of THF/MeOH/water (3 : 1 : 1, 0.01 M) followed by addition of excess palladium hydroxide on carbon. The mixture was placed under hydrogen atmosphere and stirred 2 days at rt. The mixture was then purged with nitrogen, filtered, and concentrated. The compound was brought at pH 10 by addition of dilute aqueous NaOH (1 N), and the solution was stirred for 24-48 h. Finally, the solution was purified on a sephadex column (PD-10, G- 25-M) by eluting with water. All fractions were lyophilized and analyzed by 1 H-RMN.
  • fractions containing product were purified further in a reverse phase cartridge (Sep- Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA) by eluting with water. All fractions were lyophilized and analyzed by 1 H-RMN.
  • a reverse phase cartridge Sep- Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA
  • fractions containing product were purified further in a reverse phase cartridge (Sep-Pack® Cl 8 cartridge, 1 g, Waters Corp., Milford, MA, USA) by eluting with water. All fractions were lyophilized and analyzed by 1 H-RMN.
  • a reverse phase cartridge Sep-Pack® Cl 8 cartridge, 1 g, Waters Corp., Milford, MA, USA
  • Step 2 4,6-O-bis(2-(4-Acetylpiperazin-l-yl)ethyl)-2-O-tert-butyldimethylsilyl- 1,3,5-O-methylidyne-myo-inositol (11-17): To a solution of (34) (279 mg, 0.61 mmol) in DMF (0.2 M) at 0°C, NaH (55.7 mg, 1.39 mmol) was added. When the addition was complete, the mixture was stirred for 5 min at rt. Finally, a solution of (20) (309 mg, 1.62 mmol) in DMF (3.2 mL) was added.
  • NMR spectra were recorded on an Agilent VNMRS-400 ( 1 H at 400.10 MHz and 31 P at 162 MHz). In 1 H-NMR chemical shifts were expressed in ppm relative to TMS and coupling constant (J) in Hz. In 31 P NMR no internal standard was used to collect the phosphorous NMR spectra. The usual internal standard is phosphoric acid, but this was not used due to concerns that it would affect the 1 H-NMR.
  • Condition A High-performance Liquid Chromatography (HPLC) 2795 Alliance Waters Aquity coupled to Detector DAD Agilent 1100 and Detector MS Waters ESI triple cuadrupolo Quattro micro, 10 pL of sample in MeOH was injected.
  • Mass spectroscopy (MS) analyzed by FIA (flux injected analysis) coupled to LCT Premier Orthogonal Accelerated Time of Flight Mass Spectrometer, acquiring data by electrospray ionization (ESI) in positive mode. Spectra have been scanned between 50 and 1500 Da with values every 0.2 seconds and peaks are given m/z (% of basis peak).
  • Stationary phase ZORBAX Extend-C18 3.5 pm 2.1 x 50 mm (T a 35°C).
  • IP4-4,6 substituted derivatives e.g., Compounds 1 to 53
  • the in vitro efficacy of the IP4-4,6 substituted derivatives (e.g., Compounds 1 to 53) of the invention on the inhibition of calcium phosphate crystallization in human plasma samples was evaluated according to a spectrophotometric assay previously described in the art (Ferrer M, et al., Sci Rep 2017; 7:6858, doi: 10.1038/s41598-017- 07203 -x).
  • a 96-well plate was employed. Plasma was spiked (1 volume of the IP4-4,6 substituted derivatives of the invention per 19 volumes of plasma) with increasing concentrations of the derivatives in the range of 0 - 100 pM. Plasma was then centrifuged at 10,000 g at rt and subsequently mixed with a mixture of 5 mM hydrogen phosphate and 41.67 mM calcium to attain final concentrations of 1.5 mM phosphate and 12.5 mM calcium, respectively. All reagent solutions were filtered, and pH adjusted to 7.4.
  • Plasma crystallization was assessed based on slope measurement in the linear range between 6 and 24 min from plots of increase in absorbance versus logarithm of time.
  • the efficacy of different myo-inositol phosphates derivatives in preventing in vitro formation of calcium phosphate crystals was assessed in human plasma samples using the slopes obtained between 6- and 24-min. Inhibition of crystallization was measured by comparing the slopes of the control sample (blank plasma) with those of samples containing the inhibitor as shown below:
  • Rat model addressing multiple ectopic calcification related conditions
  • Animals in groups 3, 4, and 5 were administered 5 mg/kg, 15 mg/kg, and 45 mg/kg, respectively, of Compound 27 (754.45 g/mol free acid) daily in physiological saline solution (2 mL/kg) from DI to D13 via subcutaneous route.
  • the animals were exsanguinated before sacrifice. Their necropsies were performed, and their whole right and left femoral arteries, left and right carotids, aorta, heart, and right kidney were collected for calcium content measurement. The tissues were lyophilized for 24 h and weighed. The lyophilized tissues were then digested using a 1 : 1 HNO3:HC1O4 mixture in a dry bath incubator for 2-4 h at 180°C.
  • the digested tissues were subsequently diluted using ultra-pure Milli-Q water (MilliporeSigma, Merck KGaA, Burlington, MA, US) to a final volume of 5 mL (for femoral and carotid) or 10 mL (for heart, kidney and aorta).
  • Calcium content was quantified via inductively coupled plasma optical emission spectrometry (ICP-OES) using an Optima 7300 DV ICP-OES System spectrometer (PerkinElmer, Inc., Waltham, MA, US) according to the manufacturer’s instructions.
  • ICP-OES inductively coupled plasma optical emission spectrometry
  • BP Blood perfusion
  • PeriCam PSI Normal Resolution analyzer Perimed AB, Jarfalla, SE. Measurements were taken for all groups at DO, D4, and D13.
  • the perfusion ratio i.e., mean of the two legs was calculated by comparing the baseline and either D4 or D13 readings for each group. In addition, the perfusion ratio was calculated by comparing group 1 and groups 2-5.
  • the animals were acclimatized to the treadmill for two days before conducting the test. On the first day, animals were exercised for 5 to 10 minutes with the treadmill speed ranging progressively from 15 m/min to 24 m/min. On the second day, the animals were exercised for 20 minutes as follows: (a) at 15 m/min for the first 5 minutes, (b) at 19.8 m/min for the second 5 minutes and (c) at 24 m/min for the last 10 minutes. Preoperative walking time and distance recordings were obtained. Animals that did not comply with the protocol were excluded from the test. Forty-eight rats (48) were screened for the walking ability test. The selected animals were further exercised for 5-10 minutes the day before the DO test for ensuring their treadmill habituation.
  • the protocol for MWT and MWD measurements at DO, D5, and D10 was as follows: [468] For group 2, the treadmill assessment started 15 min after dosing. For groups 2-5, the treadmill assessment started 25 min after dosing. Rats were kept running for 40 min or until fatigue. The test was stopped when the rats remained on the shock grid for five continuous seconds (i.e., fatigue). MWD (in meters) and MWT (in minutes) were recorded for each animal.
  • Stiffening of the aorta leads to decreased filling of the coronary vessels during diastole and reduced perfusion of the myocardium, indicating that Compound 27 could be used in coronary disease or coronary artery disease.
  • Decreased coronary filling can lead to the inability of the myocardium to adequately respond to increased oxygen demand resulting in ischemia, even in the absence of coronary artery obstruction.
  • Inadequate response to increased myocardial oxygen demand can lead to symptoms of myocardial ischemia and angina.
  • Compound 27 could be used in myocardial ischemia and angina pectoris (including chronic stable angina) due to its impact on aortic calcification and consequently, all the downstream effects towards ischemia and chest pain.
  • Arterial stiffening also forces the heart to pump harder and hypertrophy, indicating that Compound 27 could be used in left ventricular hypertrophy.
  • arterial stiffening and heart hypertrophy may lead to arrhythmias, heart failure, congestive heart failure, cardiac disease, cardiovascular mortality or cardiac death, indicating that Compound 27 could be used in these situations or conditions.
  • Stiffening leads to decreased filling of the coronary vessels during diastole and reduced perfusion of the myocardium, indicating that Compound 27 could be used in coronary disease or coronary artery disease.
  • Decreased coronary filling can lead to the inability of the myocardium to adequately respond to increased oxygen demand resulting in ischemia, even in the absence of coronary artery obstruction.
  • Inadequate response to increased myocardial oxygen demand can lead to symptoms of myocardial ischemia and angina.
  • Compound 27 could be used in myocardial ischemia and angina pectoris (including chronic stable angina) due to its impact on coronary artery calcification in the heart and consequently, all the downstream effects towards ischemia and chest pain.
  • Arterial stiffening also forces the heart to pump harder and hypertrophy, indicating that Compound 27 could be used in left ventricular hypertrophy.
  • coronary artery stiffening, and heart hypertrophy are settings for arrhythmias, heart failure, congestive heart failure, cardiac disease, cardiovascular mortality or cardiac death, indicating that Compound 27 could be used in these situations or conditions.
  • the recovery in blood perfusion with Compound 27 indicates that it could be used to treat PAD, including limb ischemia or critical limb ischemia.
  • the overall results in femoral calcification and blood perfusion, that lead to a functional improvement, as assessed by the maximum walking distance, indicate that Compound 27 could be used in peripheral vascular disease or peripheral arterial disease.
  • IP4-4,6 derivatives in the prevention and treatment of calcinosis cutis and calciphylaxis (CUA) induced by vitamin D3 and FeCh in a rat model was used.
  • the model evaluated the effects of Compound 27 and IP6 on the formation of calcified skin plaques in rats for a duration of 8 days. Animals were sensitized at low concentration (LC, 35,000 lU/kg) and high concentration (HC, 50,000 lU/kg) doses of vitamin D3. A FeCh solution (0.5 mg/kg) was used as challenger to induce the formation of skin plaques. All animals were weighed every day before treatment.
  • Group 1 - Control (sham), 6 animals. Animals in group 1 were administered subcutaneously physiological saline (0.9% (w/v) NaCl solution daily from DI to D3 in the interscapular space, and with one saline 0.9% injection at each of the two ventral sites in the thorax on D4. Animals in group 1 were not administered Vit D or FeCh solutions.
  • Group 3 - Compound 27 60 mg/kg LC Vit D 35,000 lU/kg, 0.5 mg/kg FeCh, 10 animals. Vit D at dose 35,000 lU/kg was administered subcutaneously x 3 consecutive days (DI, D2, D3), and one 0.5 mg/kg FeCh injection at each of the two ventral sites in the thorax on D4. This group received a daily Compound 27 s.c. treatment at 60 mg/kg dose (DI to D8).
  • Vit D at dose 50,000 lU/kg was administered subcutaneously x 3 consecutive days (DI, D2, D3), and one 0.5 mg/kg FeCh injection at each of the two ventral sites in the thorax on D4. This group received a daily IP6 s.c. treatment at 60 mg/kg dose (DI to D8).
  • Group 8 - Compound 27 100 mg/kg HC, Vit D 50,000 lU/kg, 0.5 mg/kg FeCh, 12 animals.
  • Vit D at dose 50,000 lU/kg was administered subcutaneously x 3 consecutive days (DI, D2, D3), and one 0.5 mg/kg FeC13 injection at each of the two ventral sites in the thorax on D4.
  • This group received a daily Compound 27 s.c. treatment at 100 mg/kg dose (DI to D8).
  • ICP-OES inductively coupled plasma optical emission spectrometry
  • Optima 7300 DV ICP-OES System spectrometer PerkinElmer, Inc., Waltham, MA, US
  • IP4-4,6 derivatives in the treatment of calcified aortic human valves was analyzed using an in vitro model (Zabirnyk A, et al., Vase Pharmacol 2019; 122-123, 106583, doi: 10.1016/j.vph.2019.106583).
  • the model evaluated the effects of IP6, Compound 1, Compound 3, and Compound 6 on the calcification of interstitial cells from aortic human valves (VIC).
  • the pellet was washed in 10 mL of fresh DMEM and centrifuged as described previously. The supernatant was removed by aspiration, the cell pellet was resuspended in basic growth media and seeded in 75 cm 3 flasks. VIC were cultured at 37 °C and 5% CCh with growth media changed twice a week until they reached -90% confluency. Cells were passaged at ratio of 1 :2, propagated and frozen.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés substitués en IP4-4,6 destinés à être utilisés dans la prévention, l'inhibition de la progression, et le traitement (a) de la calcification ectopique et des conséquences de celle-ci, et (b) d'une maladie et/ou d'une affection liée à la calcification ectopique et des conséquences de celle-ci. L'invention concerne également des procédés, des compositions pharmaceutiques et des formulations, des procédés d'utilisation, des articles manufacturés et des kits destinés à être utilisés dans la prévention, l'inhibition de la progression, et le traitement (a) de la calcification ectopique et des conséquences de celle-ci, et (b) d'une maladie et/ou d'un état lié à la calcification ectopique et des conséquences de celle-ci.
PCT/EP2023/071128 2022-07-29 2023-07-31 Composés dérivés substitués en ip4-4,6 destinés à être utilisés dans le traitement, l'inhibition de la progression et la prévention de la calcification ectopique WO2024023359A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22382738.7 2022-07-29
EP22382738 2022-07-29

Publications (1)

Publication Number Publication Date
WO2024023359A1 true WO2024023359A1 (fr) 2024-02-01

Family

ID=82786438

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/071128 WO2024023359A1 (fr) 2022-07-29 2023-07-31 Composés dérivés substitués en ip4-4,6 destinés à être utilisés dans le traitement, l'inhibition de la progression et la prévention de la calcification ectopique

Country Status (1)

Country Link
WO (1) WO2024023359A1 (fr)

Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4755612A (en) * 1987-07-20 1988-07-05 Merck & Co., Inc. Intermediate compounds resulting from method for forming a dihydrogen-phosphate inositol
WO1990011757A1 (fr) 1989-04-11 1990-10-18 Depomed Systems, Inc. Forme de posologie orale de medicament a liberation entretenue
WO1993018755A1 (fr) 1992-03-25 1993-09-30 Depomed Systems, Incorporated Formes galeniques de medicament oral a liberation prolongee a base de cellulose a substitution alkyle
US5582837A (en) 1992-03-25 1996-12-10 Depomed, Inc. Alkyl-substituted cellulose-based sustained-release oral drug dosage forms
WO1997047285A1 (fr) 1996-06-10 1997-12-18 Depomed, Inc. Systeme a caracteristiques de retention renforcees pour l'administration controlee par voie orale de medicaments a retention gastrique
WO1998011879A1 (fr) 1996-09-19 1998-03-26 Depomed, Inc. Formes galeniques orales retenues dans l'estomac, pour la liberation controlee de medicaments faiblement solubles et de substance insoluble
WO1998055107A1 (fr) 1997-06-06 1998-12-10 Depomed, Inc. Formes de dosage de medicaments administres par voie orale a retention gastrique pour liberation lente de medicaments hautement solubles
WO2001032217A2 (fr) 1999-11-02 2001-05-10 Depomed, Inc. Declenchement pharmacologique du mode par ingestion pour une administration amelioree de medicaments dans l'estomac
WO2001056544A2 (fr) 2000-02-04 2001-08-09 Depomed, Inc. Forme posologique enveloppe et noyau approchant la liberation d'ordre zero du medicament
WO2001097783A1 (fr) 2000-06-20 2001-12-27 Depomed, Inc. Comprimes destines a accroitre la retention gastrique de formes posologiques orales gonflantes a liberation controlee
WO2002032416A2 (fr) 2000-10-17 2002-04-25 Depomed, Inc. Inhibition d'effet emetique de metformine avec des antagonistes du recepteur 5-ht3
WO2002096404A1 (fr) 2001-05-29 2002-12-05 Depomed Development Ltd Methode de traitement de reflux gastroesophagien pathologique et de secretion d'acide nocturne
US20030039688A1 (en) 1997-06-06 2003-02-27 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
WO2003035040A1 (fr) 2001-10-25 2003-05-01 Depomed, Inc. Methodes de traitement a l'aide d'un dosage de gabapentine a retenue gastrique
WO2003035039A1 (fr) 2001-10-25 2003-05-01 Depomed, Inc. Traitement utilisant une dose posologique de losartan a retention gastrique
WO2003035041A1 (fr) 2001-10-25 2003-05-01 Depomed, Inc. Forme posologique a administration orale a retention gastrique a liberation limitee dans le tractus gastro-intestinal inferieur
WO2003035029A1 (fr) 2001-10-25 2003-05-01 Depomed, Inc. Formulation d'une forme posologique erodable a administration orale et a retention gastrique utilisant des donnees d'essai de desintegration in vitro
WO2003035177A2 (fr) 2001-10-25 2003-05-01 Depomed, Inc. Melanges polymeres optimaux pour comprimes a retention gastrique
US20030147952A1 (en) 2002-02-01 2003-08-07 Depomed, Inc. Manufacture of oral dosage forms delivering both immediate-release and sustained-release drugs
US20070066574A1 (en) 2003-11-07 2007-03-22 Felicia Grases Freixedas Myo-inositol hexaphosphate for topical use
US8377909B2 (en) 2006-06-01 2013-02-19 Universitat De Les Illes Balears Use of phytate as agent inhibiting dissolution of crystals of calcium salts for the prevention of osteoporosis
US8778912B2 (en) 2008-08-06 2014-07-15 Universitat De Les Illes Balears Composition of dialysis liquid comprising crystallisation inhibitor substances
US9612250B2 (en) 2011-10-06 2017-04-04 Laboratorios Sanifit, S.L. Method for the direct detection and/or quantification of at least one compound with a molecular weight of at least 200
WO2017098047A1 (fr) * 2015-12-11 2017-06-15 ETH Zürich Dérivés d'inositol à utiliser dans la cristallisation pathologique
WO2020074944A1 (fr) * 2018-10-11 2020-04-16 Sanifit Therapeutics S.A. Phosphates d'inositol pour le traitement de la calcification ectopique
WO2022162206A1 (fr) * 2021-01-29 2022-08-04 Sanifit Therapeutics, S.A. Composés dérivés substitués par ip4-4,6

Patent Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4755612A (en) * 1987-07-20 1988-07-05 Merck & Co., Inc. Intermediate compounds resulting from method for forming a dihydrogen-phosphate inositol
WO1990011757A1 (fr) 1989-04-11 1990-10-18 Depomed Systems, Inc. Forme de posologie orale de medicament a liberation entretenue
US5007790A (en) 1989-04-11 1991-04-16 Depomed Systems, Inc. Sustained-release oral drug dosage form
WO1993018755A1 (fr) 1992-03-25 1993-09-30 Depomed Systems, Incorporated Formes galeniques de medicament oral a liberation prolongee a base de cellulose a substitution alkyle
US5582837A (en) 1992-03-25 1996-12-10 Depomed, Inc. Alkyl-substituted cellulose-based sustained-release oral drug dosage forms
WO1997047285A1 (fr) 1996-06-10 1997-12-18 Depomed, Inc. Systeme a caracteristiques de retention renforcees pour l'administration controlee par voie orale de medicaments a retention gastrique
US5972389A (en) 1996-09-19 1999-10-26 Depomed, Inc. Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter
WO1998011879A1 (fr) 1996-09-19 1998-03-26 Depomed, Inc. Formes galeniques orales retenues dans l'estomac, pour la liberation controlee de medicaments faiblement solubles et de substance insoluble
WO1998055107A1 (fr) 1997-06-06 1998-12-10 Depomed, Inc. Formes de dosage de medicaments administres par voie orale a retention gastrique pour liberation lente de medicaments hautement solubles
US6340475B2 (en) 1997-06-06 2002-01-22 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
US20020051820A1 (en) 1997-06-06 2002-05-02 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
US20030039688A1 (en) 1997-06-06 2003-02-27 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
WO2001032217A2 (fr) 1999-11-02 2001-05-10 Depomed, Inc. Declenchement pharmacologique du mode par ingestion pour une administration amelioree de medicaments dans l'estomac
US20030044466A1 (en) 1999-11-02 2003-03-06 Depomed, Inc. Pharmacological inducement of the fed mode for enhanced drug administration to the stomach
WO2001056544A2 (fr) 2000-02-04 2001-08-09 Depomed, Inc. Forme posologique enveloppe et noyau approchant la liberation d'ordre zero du medicament
US20030104062A1 (en) 2000-02-04 2003-06-05 Depomed, Inc. Shell-and-core dosage form approaching zero-order drug release
US6488962B1 (en) 2000-06-20 2002-12-03 Depomed, Inc. Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms
WO2001097783A1 (fr) 2000-06-20 2001-12-27 Depomed, Inc. Comprimes destines a accroitre la retention gastrique de formes posologiques orales gonflantes a liberation controlee
US6451808B1 (en) 2000-10-17 2002-09-17 Depomed, Inc. Inhibition of emetic effect of metformin with 5-HT3 receptor antagonists
WO2002032416A2 (fr) 2000-10-17 2002-04-25 Depomed, Inc. Inhibition d'effet emetique de metformine avec des antagonistes du recepteur 5-ht3
WO2002096404A1 (fr) 2001-05-29 2002-12-05 Depomed Development Ltd Methode de traitement de reflux gastroesophagien pathologique et de secretion d'acide nocturne
WO2003035039A1 (fr) 2001-10-25 2003-05-01 Depomed, Inc. Traitement utilisant une dose posologique de losartan a retention gastrique
WO2003035041A1 (fr) 2001-10-25 2003-05-01 Depomed, Inc. Forme posologique a administration orale a retention gastrique a liberation limitee dans le tractus gastro-intestinal inferieur
WO2003035029A1 (fr) 2001-10-25 2003-05-01 Depomed, Inc. Formulation d'une forme posologique erodable a administration orale et a retention gastrique utilisant des donnees d'essai de desintegration in vitro
WO2003035177A2 (fr) 2001-10-25 2003-05-01 Depomed, Inc. Melanges polymeres optimaux pour comprimes a retention gastrique
WO2003035040A1 (fr) 2001-10-25 2003-05-01 Depomed, Inc. Methodes de traitement a l'aide d'un dosage de gabapentine a retenue gastrique
US20030104053A1 (en) 2001-10-25 2003-06-05 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US20030147952A1 (en) 2002-02-01 2003-08-07 Depomed, Inc. Manufacture of oral dosage forms delivering both immediate-release and sustained-release drugs
US20070066574A1 (en) 2003-11-07 2007-03-22 Felicia Grases Freixedas Myo-inositol hexaphosphate for topical use
US8377909B2 (en) 2006-06-01 2013-02-19 Universitat De Les Illes Balears Use of phytate as agent inhibiting dissolution of crystals of calcium salts for the prevention of osteoporosis
US8778912B2 (en) 2008-08-06 2014-07-15 Universitat De Les Illes Balears Composition of dialysis liquid comprising crystallisation inhibitor substances
US9612250B2 (en) 2011-10-06 2017-04-04 Laboratorios Sanifit, S.L. Method for the direct detection and/or quantification of at least one compound with a molecular weight of at least 200
WO2017098047A1 (fr) * 2015-12-11 2017-06-15 ETH Zürich Dérivés d'inositol à utiliser dans la cristallisation pathologique
WO2020074944A1 (fr) * 2018-10-11 2020-04-16 Sanifit Therapeutics S.A. Phosphates d'inositol pour le traitement de la calcification ectopique
WO2022162206A1 (fr) * 2021-01-29 2022-08-04 Sanifit Therapeutics, S.A. Composés dérivés substitués par ip4-4,6

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
"Concise Dictionary of Biomedicine and Molecular Biology", 2002, CRC PRESS
"Oxford Dictionary of Biochemistry and Molecular Biology", 2000, OXFORD UNIVERSITY PRESS
ARTIACH G ET AL., CIRCULATION, vol. 142, 2020, pages 776 - 789
AUGUSTIN M ET AL., INT WOUND J., vol. 14, no. 6, 2017, pages 1299 - 1304
BATES-JENSEN B, DECUBITUS, vol. 5, no. 6, 1992, pages 20 - 28
BAUDIN GISèLE ET AL: "- myo -Inositol 1,3,4,5,-Tetraphosphate", HELVETICA CHIMICA ACTA, vol. 71, no. 5, 10 August 1988 (1988-08-10), Hoboken, USA, pages 1367 - 1378, XP055805184, ISSN: 0018-019X, DOI: 10.1002/hlca.19880710548 *
CHEN J ET AL., NEPHROL DIAL TRANSPLANT., vol. 31, no. 7, 2016, pages 1145 - 1151
FERRER M ET AL., SCI REP, vol. 7, 2017, pages 6858
GIACHELLI C, AM J PATHOL., vol. 154, no. 3, 1999, pages 671 - 67
HANBALI M. ET AL., BIOORG. MED. CHEM. LETTERS, vol. 16, no. 10, 2006, pages 2637 - 2640
HAYNES M ET AL., J. PHARMACEUTICAL SCI., vol. 94, 2005, pages 2111 - 2120
HITOSUGI S ET AL., ORGANIC LETTERS, vol. 16, no. 3, 2014, pages 844 - 847
JANKOWSKI J ET AL., CIRCULATION, vol. 143, no. 11, 2021, pages 1 157 - 1 172
KADIRVEL M ET AL., ORG. BIOMOL. CHEM., vol. 6, no. 11, 2008, pages 1966 - 1972
KARDIVEL M, ORG. & BIOMOLECULAR CHEM., vol. 6, no. 11, 2008, pages 1966 - 72
KEMPF H ET AL., FRONT CELL DEV BIOL., vol. 9, 2021, pages 759702
LINDMAN B ET AL., NAT REV DIS PRIMERS., vol. 2, 2016, pages 16006
MANSOUR A ET AL., FRONT. CELL DEV. BIOL., vol. 8, 2020, pages 58976130
MARTIN S ET AL., J. ORG. CHEM., vol. 59, no. 17, 1994, pages 4805 - 4820
NITSCHKE Y ET AL., AM J HUM GENET., vol. 90, no. 1, 2012, pages 25 - 39
NITSCHKE Y ET AL., TRENDS CARDIOVASC MED., vol. 22, no. 6, 2012, pages 145 - 149
NORTH B ET AL., CIRC RES., vol. 110, no. 8, 2012, pages 1097 - 1108
PAK C, AM J KIDNEY DIS, vol. 18, 1991, pages 624 - 632
PXEVAN GILS M ET AL., J INVEST DERMATOL, vol. 138, 2022, pages 2333 - 2342
RAJAGOPALAN S ET AL., CIRCULATION, vol. 114, no. 18, 2006, pages 1914 - 1922
SCHANTL ANTONIA E. ET AL: "Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers", vol. 11, no. 1, 5 February 2020 (2020-02-05), pages 721, XP055908916, Retrieved from the Internet <URL:http://www.nature.com/articles/s41467-019-14091-4> DOI: 10.1038/s41467-019-14091-4 *
ZABIRNYK A ET AL., VASE PHARMACOL, vol. 122-123, 2019, pages 106583

Similar Documents

Publication Publication Date Title
JP2016034960A (ja) １，３−プロパンジスルホン酸を送達するための方法、化合物、および組成物
EP2539352B1 (fr) Derives de amp pour traiter les cardiopathies
CN105859680A (zh) 缩醛磷脂化合物、包含缩醛磷脂化合物的药物组合物和用于治疗衰老性疾病的方法
EP0916679A1 (fr) Dérivés d&#39;acides benzazepinone-N-acétiques ayant un groupe phosphonique, leur procédé de préparation et médicaments contenant lesdits composés
KR20110044947A (ko) 과잉활성 면역계 치료를 위한 사이클로리그난의 용도
US20240109924A1 (en) Ip4-4,6 substituted derivative compounds
US20140155334A1 (en) Polyphosphate and pyrophosphate derivative of saccharides
WO2024023359A1 (fr) Composés dérivés substitués en ip4-4,6 destinés à être utilisés dans le traitement, l&#39;inhibition de la progression et la prévention de la calcification ectopique
IL291891A (en) Prodrug of myeloperoxidase inhibitors
CN113004356B (zh) 新型京尼平衍生物，及其制备方法和应用
JP7053762B2 (ja) Ｓａｐ枯渇剤としてのｄ－プロリン誘導体
JPH09506640A (ja) ヘテロアリール基置換デオキシグリセロ−ホスホエタノールアミン
CN117083065A (zh) 肌肉减少症相关疾病等的新颖治疗和预防
CA3003741A1 (fr) Conjugues de bortezomib et leurs methodes d&#39;utilisation
AU2017405304B2 (en) Heparan sulfate glycomimetic compounds and their pharmaceutical and cosmeceutical uses
CA3130735A1 (fr) Composes de phosphate d&#39;inositol pour une utilisation dans l&#39;augmentation de la perfusion tissulaire
KR20150014910A (ko) 허혈-재관류계 질환의 치료 화합물
CN109824574B (zh) 吲哚-3-甲酰胺类化合物及其应用
US20210023055A1 (en) Mofezolac derivatives as multi-functions selective cox-1 inhibitors
WO2024023360A1 (fr) Composés substitués par ip5
WO2016147185A1 (fr) Dérivés d&#39;adénosine thiophosphate et leurs utilisations
WO2019111896A1 (fr) Agent antiprurigineux
WO2014084744A1 (fr) Composés agglomérés dendritiques saccharidiques comme inhibiteurs de bace-1
JP2019099505A (ja) 脳血管障害治療剤
EP1847270A1 (fr) Utilisation d&#39;analogues de l&#39;amigdaline pour le traitement de la psoriasis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23750980

Country of ref document: EP

Kind code of ref document: A1