WO2023129141A1 - Compositions de dérivés de ménaquinol biologiquement actifs et méthodes de traitement - Google Patents

Compositions de dérivés de ménaquinol biologiquement actifs et méthodes de traitement Download PDF

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WO2023129141A1
WO2023129141A1 PCT/US2021/065401 US2021065401W WO2023129141A1 WO 2023129141 A1 WO2023129141 A1 WO 2023129141A1 US 2021065401 W US2021065401 W US 2021065401W WO 2023129141 A1 WO2023129141 A1 WO 2023129141A1
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mammal
menaquinol
administration
vitamin
mixture
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PCT/US2021/065401
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John M. RUDEY
Eric Stephen GRUFF
Sam L. NGUYEN
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Epizon, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/40—Succinic acid esters

Definitions

  • the present invention relates to biologically active menaquinol derivatives, compositions and formulations, and combinations thereof, for the treatment of diseases associated with vitamin K, its reduced and bioactive form menaquinol and salts thereof, including osteoporosis and osteopenia.
  • Vitamin K is known as a group of structurally similar, fat-soluble vitamins.
  • Vitamin K 2 or menaquinone has nine related compounds that can be subdivided into the short-chain menaquinones (such as menaquinone-4 or MK-4) and the long-chain menaquinones, such as MK-7, MK-8 and MK-9 to MK-12.
  • the vitamins include phylloquinone (K1), menaquinones (K2) and menadione (K3). Plants synthesize vitamin K1 while bacteria can produce a range of vitamin K2 forms, including the conversion of K1 to K2 by bacteria in the small intestines. Vitamin K3 is a synthetic version of the vitamin, and due to its toxicity, has been banned in by the US Food and Drug Administration for human uses.
  • Vitamin K1 is preferentially used by the liver as a clotting factor.
  • Vitamin K2 is used preferentially in the brain, vasculature, breasts and kidneys. Vitamin K2 contributes to production of myelin and sphingolipids (fats essential for brain health) and protects against oxidative damage in the brain. Vitamin K2, such as MK-4, promotes bone health by stimulating connective tissue production in bone.
  • Vitamin K2 which is the main storage form in animals, has several subtypes, which differ in chain length of the isoprenoid group or residue in the side chains. These vitamin K2 homologues are called menaquinones, and are characterized by the number of isoprenoid residues in their side chains.
  • MK-4 has four isoprene residues in its side chain, and is the most common type of vitamin K2 in animal products.
  • MK-4 is normally synthesized from vitamin K1 in certain animal tissues (arterial walls, pancreas and testes) by replacement of the phytyl group with an unsaturated geranyl group containing four isoprene units. Unlike MK-4, MK-7 is not produced by human tissue.
  • MK-7 may be converted from phylloquinone (K 1 ) in the colon by E. coli bacteria.
  • MK-4 and MK-7 are sold in the U.S. in dietary supplements for bone health.
  • MK-4 has been shown to decrease the incidence of fractures.
  • MK-4, at a dose of 45 mg daily, has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.
  • Osteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density (BMD) is reduced, bone micro architecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered.
  • BMD bone mineral density
  • osteoporosis in women as a bone mineral density 2.5 standard deviations below peak bone mass, that is, for an average 30-year-old healthy female. Osteoporosis is most common in women after menopause (referred to as postmenopausal osteoporosis). Osteoporosis may also develop in men, and may occur in anyone in the presence of particular hormonal disorders and other chronic diseases or as a result of medications, specifically glucocorticoids, when the disease is called steroid- or glucocorticoid-induced osteoporosis and as a result of nutritional deficiency states or other metabolic disorders, for example, hyponatremia or as a secondary consequence of cancer.
  • Osteopenia is a condition where bone mineral density is lower than normal, and is considered by many doctors to be a precursor to osteoporosis.
  • the underlying mechanism in most cases of osteoporosis is an imbalance between bone resorption and bone formation.
  • the three main mechanisms by which osteoporosis develops include an inadequate peak bone mass (the skeleton develops insufficient mass and strength during growth), excessive bone resorption and inadequate formation of new bone during remodelling.
  • Hormonal factors strongly determine the rate of bone resorption; lack of estrogen (e.g., as a result of menopause) increases bone resorption as well as decreasing the deposition of new bone that normally takes place in weight-bearing bones.
  • CVD cardiovascular disease
  • Vitamin K including MK-7, are present in low concentrations in a typical diet. It has also been established that there exists a direct correlation between the level of vitamin K in a patient's blood and the incidence of vascular calcification, bone density and bone strength.
  • vitamin K such as MK-7 and its also fat-soluble hydroquinone (menaquinol) derivatives as disclosed herein, may provide significant clinical benefit for reducing vascular calcification noted, in part, by arterial stiffness, and increase bone mineralization or increase in bone mineral density, that will help treat or prevent CVD, and treat or prevent bone diseases in patients with CKD.
  • menaquinol fat-soluble hydroquinone
  • MK-7 Long chain menaquinones such as MK-7, MK-8 and MK-9, are found in fermented foods such as cheese, curd and sauerkraut. It has also been established that the effects of long chain MK-n such as MK-7 on normal blood coagulation is greater and longer lasting than vitamin K1 and MK-4. MK-7 has also been shown to have a long half-life in serum when compared to MK-4, providing a better carboxylation-grade of osteocalcin compared to Vitamin K1. See Sato et al., Nutrition Journal, 2012, 11:93. [0010] Nutritional doses of MK-7 can be established to be well absorbed in humans, and as a consequence, provide a significant increase in the serum for MK-7 levels.
  • the present application discloses novel and biologically effective menaquinol derivatives, including salts, and their method of use for the treatment of various diseases.
  • menaquinol derivatives including salts, and their method of use for the treatment of various diseases.
  • the present application discloses an isolated, stable and biologically active menaquinol derivative that is a carbonate dimer of the formula VIIIa.
  • the preparation of VIIIa, wherein n is 9, is shown below:
  • the application discloses a menaquinol derivative that is a carbonate dimer of the formula VIIIb, wherein n is 9.
  • the preparation of VIIIb is shown below: [0016]
  • the mono-acetate starting material in Step 1, above, for the preparation of IXc and then the preparation of VIIIb may be prepared as shown below: [0017]
  • the naphthaquinone may be reduced to the corresponding hydraquinone, which may be acylated, such as using acetic anhydride and acetyl chloride, to provide the di- acetate in high yield.
  • the diacetate may be selectively de-acetylated selectively to the corresponding mono-acetate in high yield and with high selectivity, providing >99% of the desired mono-acetate.
  • the application discloses a menaquinol derivative that is a carbonate dimer of the formula VIIIc, wherein n is 9.
  • the application discloses a compound of the formulae VIIIa.1, VIIIb.1 and VIIIc.1, wherein each R1 and R2 is independently C 1 -C 6 alkyl, or independently methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, pentyl, iso-pentyl, hexyl and iso-hexyl; and n is 9.
  • R1 and R2 are both methyl.
  • R1 and R2 are both ethyl.
  • the application discloses a menaquinol derivative of the formulae IX, IX.01 and IX.0a, where n is 9. [0021] In one variation, the application discloses a process for the preparation of the compound of the formulae IXa, IXb, IXc, IXd and IX: wherein n is 9.
  • the application discloses the compound of the formulae IX.0, X.0, X.0a, IX.1, IX.2, X.0b, X.1, X.2, and X.2a: wherein for compounds IX.0, X.0 and X.0a each R 1 and R 2 is independently C 1 -C 6 alkyl, or independently methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, pentyl, iso-pentyl, hexyl and iso-hexyl, and n is 9.
  • R 1 and R 2 are both -CH3.
  • R 1 is C 1 -C 6 alkyl.
  • R 2 is C 1 -C 6 alkyl.
  • R 1 is -CH 3 (methyl).
  • R 2 is -CH 3 .
  • n is 9.
  • each R 1 and R 2 is independently C 1 -C 6 alkyl, or independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, pentyl, iso-pentyl, hexyl and iso-hexyl, and n is 9.
  • R 1 and R 2 are both -CH 3 .
  • R 1 is C 1 -C 6 alkyl.
  • R 2 is C 1 -C 6 alkyl.
  • R 1 is - CH3 (methyl).
  • R 2 is -CH3.
  • m is 1, 2, 3, 4 or 5, and n is 9.
  • m is 1; or m is 2.
  • n is 9. [0024] In another variation of the above menaquinol derivatives, n is 9.
  • R 1 is C 1 -C 6 alkyl.
  • R 2 where present, is C 1 -C 6 alkyl.
  • each of R 1 and R 2 where present in a single molecule is independently C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, pentyl, iso-pentyl, hexyl and iso- hexyl.
  • R 1 is methyl
  • R 2 is methyl.
  • MK-9 via an Allylation Reaction and Retro-Diels-Alder Reaction: [0025]
  • the preparation of MK-9 may be performed in the general scheme as shown below.
  • the synthesis or reaction process may be performed neat, or in the absence of any organic solvents.
  • the ketone-cyclopendiene adduct may be alkylated with an excess of a selected allyl derivative, such as the allyl halide, such as an allyl bromide, or an allyl tosylate derivate or an allyl mesylate derivative, in at least about 1.2 equivalent, or at least 1.5, 2.0 or 2.5 quivalent.
  • a selected allyl derivative such as the allyl halide, such as an allyl bromide, or an allyl tosylate derivate or an allyl mesylate derivative
  • the reaction may be conducted in the presence of a base sufficient to deprotonate the bridge hydrogen, such as a metal alkoxide, such as sodium tert-butoxide or potassium tert-butoxide. While the reaction may be conducted in a solvent, such as THF or diethyl ether, the reaction may be performed neat, or in the absence of any solvent to provide the desired product in about 1 hour. Optionally, the desired product may be diluted with a solvent, such as THF, diethyl ether, hexanes or mixtures thereof, and then filtered and isolated from residual salts and by-products. Filtration of the crude product may be conducted with a short column or plug of silica gel. Removal of the solvent in vacuo provides the desired product.
  • a base sufficient to deprotonate the bridge hydrogen
  • a base such as a metal alkoxide, such as sodium tert-butoxide or potassium tert-butoxide.
  • a solvent such as THF or diethyl
  • the desired intermediate product may be used as is, or further purified, if desired.
  • the intermediate product may be placed under vacuum, such as 15 torr or less, and then heated to about 85 oC, optionally in the absence of stirring.
  • the reaction is determined to be complete over at least 5 hours or about 12 hours, using TLC or HPLC, the resulting product was purified, such as using flash column chromatography, in a solvent, such as 4%-10% diethyl ether in hexanes, and then the solvents are removed under vacuo to provide the desired MK-9 product in about 80% yield over the two reaction steps.
  • the application discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a menaquinol derivative of any one of the above embodiments and aspects, or a mixture thereof; and a pharmaceutically acceptable excipient, wherein the composition is effective for the treatment of a condition associated with vitamin K selected for the treatment of osteoporosis, arteriosclerosis, calciphylaxis or tissue calcification.
  • the application discloses a method for increasing the tissue concentration of menaquinol as a co-factor for gamma glutamate carboxylase (GGCX) for catalyzing the carboxylation of vitamin K dependent proteins that is associated with the treatment or prevention of osteoporosis, arteriosclerosis, calciphylaxis or tissue calcification in a patient in need thereof, the method comprising an administration of a therapeutically effective amount of a menaquinol derivative or a pharmaceutical composition comprising an effective amount of a menaquinol derivative as disclosed above, or a mixture thereof.
  • GGCX gamma glutamate carboxylase
  • the administration of the menaquinol derivative overcomes the oxidative block in patients with CKD and in patients receiving hemodialysis and provides maximal levels of menaquinol and maximal benefits at the tissue level.
  • the tissue is the skin or dermis tissue.
  • the tissue is at least of of the patient’s mitral valve, the patient’s artic valve and blood vessels.
  • the menaquinol is menaquinol-9.
  • the method increases the tissue concentration of menaquinol by at least 20%, 30%, 40%, 50%, 100%, 150%, 200%, 250%, 300%, 400% or 500% or more when compared to the administration of menaquinone.
  • the application discloses a method for the treatment of a disease in a mammal selected from the group consisting of neurodegenerative diseases, retinopathy, rheumatoid polyarthritis, atherosclerosis, amyotrophic lateral sclerosis, cerebral ischemia, cataracts, systemic infections, pathologies associated with cutaneous aging and with senescence in tissues, pathologies associated with mitochondrial dysfunction, cachexia associated with under nutrition, wherein the treatment is associated with the increase in the longevity of mammals, the method comprises the administration of a therapeutically effective amount of a compound or composition comprising a menaquinol derivative of the formulae formulae VIII to XI, inclusive of all disclosed compounds herein, or a mixture thereof.
  • the application discloses a method for treating a mammal with a disease selected from the group consisting of vitamin K deficiency, osteoporosis, a proliferative disease, and a cardiovascular disease, comprising administering to the mammal a therapeutically effective amount of a menaquinol derivative as disclosed above, or a mixture thereof.
  • the proliferative disease is selected from the group consisting of cancer, leukemia and an inflammatory disease.
  • the application discloses a method for the treatment or prevention of osteoporosis and/or osteopenia, the method comprising administering to a patient in need of treatment, a therapeutically effective amount of a composition comprising a menaquinol derivative of the formulae VIII to XI, inclusive of all disclosed compounds herein, or a mixture thereof.
  • the application disloses a method of treating, preventing, slowing the progression of, arresting, and/or reversing calciphylaxis in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a composition comprising substantially pure menaquinol derivative of the formulae VIII to XI, inclusive of all disclosed compounds herein, or a mixture thereof, and a pharmaceutically acceptable excipient, to prevent, slow the progression of, arrest, or reverse calciphylaxis.
  • the mammal has distal calciphylaxis and/or central calciphylaxis.
  • the mammal has diabetes, chronic kidney disease or end stage renal disease. In another aspect of the method, the mammal has stage 3, stage 4 or stage 5 chronic kidney disease. In another aspect of the methods, the mammal is undergoing hemodialysis. In yet another aspect of the method, the mammal is receiving non-warfarin-based anti-coagulant therapy. In another aspcet of the method, the anti-coagulant therapy is oral anti-coagulation therapy.
  • the anti-coagulation therapy comprises an inhibitor of Factor Xa activity selected from apixaban, rivaroxaban, betrixaban, edoxaban, otamixaban, letaxaban, eribaxaban or fondaparinux; or Factor IIa activity selected from dabigratran or argatroban.
  • the mammal has chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the mammal has a calciphylaxis-related dermal lesion.
  • the administration of the composition reduces the total surface area of the dermal lesion by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.
  • the administration of the compound of the formulae VIII to XI, inclusive of all disclosed compounds herein, or a mixture thereof, to the mammal increases the mammal’s serum T50 value by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% relative to the mammal’s serum T50 value prior to administration of the above compound, or a mixture thereof.
  • the administration of the compound of the formulae VIII to XI, inclusive of all disclosed compounds herein, or a mixture thereof increases a ratio of a carboxylated to a non-carboxylated of a Vitamin K dependent protein in plasma of the mammal after administration of the composition is greater than prior to administration of the composition.
  • a method of treating, preventing, slowing the progression of, arresting and/or reversing tissue calcification in a pre-diabetic mammal (or subject) with diabetes, chronic kidney disease or a combination thereof, and in need thereof comprising administering to the mammal at least 50 mg of a compound of the formulae VIII to XI, inclusive of all disclosed compounds herein, or a mixture thereof per day, to prevent, slow the progression of, and/or arrest tissue calcification, wherein the above compound, or a mixture thereof, is administered in a pharmaceutical composition.
  • the specification also discloses the recited compounds or compositions thereof, for use as a medicament in the treatment of the recited medical conditions or diseases; and the specification discloses the use of the recited compounds in the manufacture of a formulation or medicament for the treatment of the disclosed medical conditions or diseases.
  • the menaquinol derivative is administered at a dose of at least 10 mg, 20 mg, 30 mg, 40 mg or 50 mg.
  • the menaquinol derivative is administered at a dose of at least 100 mg, 150 mg, 200 mg, 25 mg, 300 mg, 350 mg, 400 mg 450 mg or 500 mg.
  • the menaquinol derivative is administered at a dose of at least 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1,000 mg or more.
  • the mammal has diabetes.
  • the mammal has type II diabetes.
  • the mammal has been diagnosed as pre-diabetic.
  • the mammal has chronic kidney disease.
  • the mammal has stage 4 or 5 chronic kidney disease/end stage renal disease.
  • the mammal is undergoing hemodialysis.
  • the mammal is receiving non-warfarin based anti-coagulant therapy.
  • the anti-coagulant therapy is oral anti-coagulation therapy.
  • anti-coagulation therapy comprises an inhibitor of Factor Xa activity selected from apixaban, rivaroxaban, betrixaban, edoxaban, otamixaban, letaxaban, eribaxaban or fondaparinux; or Factor IIa activity selected from dabigratran or argatroban.
  • the application discloses a method of treating, preventing, slowing the progression of, arresting, and/or reversing tissue calcification in a mammal undergoing hemodialysis, and in need thereof, the method comprising administering to the mammal at least 10 mg of the compound of the formulae VIII to XI, inclusive of all disclosed compounds herein, or a mixture thereof, per day, thereby to prevent, slow the progression, arrest, and/or reverse tissue calcification, wherein the above compound, or a mixture thereof is administered in a pharmaceutical composition.
  • the menaquinol derivative is administered at a dose of at least 10 mg, 20 mg, 30 mg, 40 mg or 50 mg.
  • the menaquinol derivative is administered at a dose of at least 100 mg, 150 mg, 200 mg, 25 mg, 300 mg, 350 mg, 400 mg 450 mg or 500 mg. In another variation, the menaquinol derivative is administered at a dose of at least 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1,000 mg or more. In another aspect of the above method, the mammal has diabetes.
  • the application discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a menaquinol derivative (or also referred to as “a compound” or “disclosed compound(s)”) as disclosed above, or a mixture thereof, and a pharmaceutically acceptable excipient, wherein the composition is effective for the treatment of a condition associated with vitamin K selected from for the treatment of osteoporosis and arteriosclerosis.
  • the present application discloses a method for the treatment of a disease in a mammal selected from the group consisting of neurodegenerative diseases, retinopathy, rheumatoid polyarthritis, atherosclerosis, amyotrophic lateral sclerosis, cerebral ischemia, cataracts, systemic infections, pathologies associated with cutaneous aging and with senescence in tissues, pathologies associated with mitochondrial dysfunction, cachexia associated with under nutrition, wherein the treatment is associated with the increase in the longevity of mammals, the method comprises the administration of a therapeutically effective amount of a compound or composition comprising a menaquinol compound as disclosed above, or a mixture thereof.
  • a method for treating a mammal with a disease selected from the group consisting of vitamin K deficiency, osteoporosis, a proliferative disease, and a cardiovascular disease comprising administering to the mammal a therapeutically effective amount of a compound as disclosed herein, or a mixture thereof.
  • the proliferative disease is selected from the group consisting of cancer, leukemia and an inflammatory disease.
  • a method for the treatment or prevention of osteoporosis and/or osteopenia comprising administering to a patient in need of treatment, a therapeutically effective amount of a composition comprising a compound as disclosed above, or a mixture thereof.
  • the disclosed method for the administration of MK-7 and its fat-soluble hydroquinone derivatives, or combinations thereof may be used in the treatment or reduction of vascular calcification, increase in bone mineral density and for the treatment, reduction or prevention of bone diseases, such as in patients with CKD.
  • a method of treating, preventing, slowing the progression of, arresting, and/or reversing calciphylaxis in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a composition comprising substantially pure menaquinol compound as disclosed herein, and a pharmaceutically acceptable excipient, to prevent, slow the progression of, arrest, or reverse calciphylaxis.
  • the mammal has distal calciphylaxis and/or central calciphylaxis.
  • the mammal has diabetes, chronic kidney disease or end stage renal disease.
  • the mammal has stage 3, stage 4 or stage 5 chronic kidney disease.
  • the mammal is undergoing hemodialysis. In yet another aspect, the mammal is receiving non-warfarin-based anti-coagulant therapy.
  • the anti-coagulant therapy is oral anti- coagulation therapy.
  • the anti-coagulation therapy comprises an inhibitor of Factor Xa activity selected from apixaban, rivaroxaban, betrixaban, edoxaban, otamixaban, letaxaban, eribaxaban or fondaparinux; or Factor IIa activity selected from dabigratran or argatroban.
  • the mammal has chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the mammal has a calciphylaxis-related dermal lesion.
  • administration of the composition reduces the total surface area of the dermal lesion by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.
  • administration of the substantially pure compound as disclosed herein, to the mammal increases the mammal’s serum T50 value by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) relative to the mammal’s serum T50 value prior to administration of the disclosed compound.
  • administration of the disclosed compound increases a ratio of a carboxylated to a non-carboxylated of a Vitamin K dependent protein in plasma of the mammal after administration of the composition is greater than prior to administration of the composition.
  • the increase of the ratio of a carboxylated to a non-carboxylated of a Vitamin K dependent protein in plasma of the mammal after administration of the composition is by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to the ratio prior to administration.
  • the administration of the disclosed compounds decreases the amount of a non-carboxylated Vitamin K-dependent protein in the subject’s plasma, for example, by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% relative to the amount prior to administration of the compounds.
  • the Vitamin K-dependent protein is selected from Matrix Gla Protein (MGP), Growth Arrest Specific Gene 6 (Gas-6) protein, PIVKA-II protein, osteocalcin, activated Protein C, activated Protein S, factor II, factor VII, factor IX and factor X.
  • the administration of the compounds increases the plasma level of osteoprotegerin or Fetuin A, for example, by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to the plasma concentration of osteoprotegerin or Fetuin A prior to administration of the compounds.
  • the administration of the compounds decreases the plasma level of D-Dimer or Highly Sensitive C Reactive Peptide (hs-CRP), for example, by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% relative to the plasma concentration of D-Dimer or Highly Sensitive C Reactive Peptide (hs-CRP) prior to administration of the compounds.
  • the method may include administering from about 20 mg to about 750 mg of the compound to the subject per day. In other variations, the method may include administering from about 50 mg to about 750 mg of the compound to the subject per day.
  • the method may include administering from about 20 mg to about 500 mg of the compound to the subject per day. In other variations, the method may include administering from about 50 mg to about 500 mg of the compound to the subject per day. In certain variations, the method can include administering from about 20 mg to about 250 mg of the compound to the subject per day. In other variations, the method may include administering from about 10 mg to about 250 mg of the compound to the subject per day. In other variations, the method may include administering from about 20 mg to about 100 mg of the compound to the subject per day. In other variations, the method may include administering from about 50 mg to about 100 mg of the compound to the subject per day.
  • the method may include administering from about 10 mg to about 75 mg of the compound to the subject per day, for example, administering 10, 25, 50, 75, 100, 200, 300, 400 or 500 mg of the compound to the subject per day.
  • the compound is administered to the subject for at least 2 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 6 months, 1 year, or indefinitely as needed. If the subject is undergoing hemodialysis, the compound may be administered to the subject for a period that includes at least the duration of hemodialysis.
  • a biopsy may be taken of the relevant lesions using von Kassa Staining to determine tissue levels of PTH and evidence of change in calcium and phosphate deposition in dermal arterioles.
  • the presence of a uremic oxidative blockade is determined by measuring increased plasma lipid peroxidation, e.g., by detection of increased F2 isoprostanes, increased isolevuglandin-plasma protein adducts; increased protein and amino acid oxidation, e.g., by detection of tyrosine residue oxidation, cysteine or methionine residue oxidation, lysine oxidation and threonine oxidation, thiol oxidation and carbonyl formation in plasma proteins; reactive aldehyde formation, e.g., by detecting glyoxal, methylglyoxal, acrolein, glycoaldehyde, and parahydroxy phenacetaldehyde; increased reactive carbonyl compounds, e.g., by measuring hydrazine formation after reaction with 2,4- dinitrophenylhydrazine; diminished plasma glutathione levels and glutathione peroxid
  • the mammal has diabetes.
  • the mammal has type II diabetes; or the mammal has been diagnosed as pre-diabetic.
  • the mammal has chronic kidney disease.
  • the mammal has stage 4 or 5 chronic kidney disease/end stage renal disease.
  • the mammal is undergoing hemodialysis.
  • the mammal is receiving non-warfarin based anti-coagulant therapy.
  • the anti-coagulant therapy is oral anti-coagulation therapy.
  • the anti-coagulation therapy comprises an inhibitor of Factor Xa activity selected from apixaban, rivaroxaban, betrixaban, edoxaban, otamixaban, letaxaban, eribaxaban or fondaparinux; or Factor IIa activity selected from dabigratran or argatroban.
  • a method of treating, preventing, slowing the progression of, arresting, and/or reversing tissue calcification in a mammal undergoing hemodialysis, and in need thereof comprising administering to the mammal at least 2 mg of substantially pure compound as disclosed herein per day, thereby to prevent, slow the progression, arrest, and/or reverse tissue calcification, wherein the disclosed compound is administered in a pharmaceutical composition.
  • the mammal has diabetes.
  • Vitamin K Metabolism Development of vascular and soft tissue calcification following the failure to regenerate reduced forms of vitamin K: Vitamin K is an essential enzymatic co-factor that is required for posttranslational modifications of vitamin K dependent (VKD) proteins.
  • VKD proteins While there are numerous VKD proteins many are clinically relevant to ESRD patients. They include central coagulation factors such as factors II, VII, IX and X as well as intercellular matrix proteins including Matrix GLA-1 and Osteocalcin.
  • central coagulation factors such as factors II, VII, IX and X
  • intercellular matrix proteins including Matrix GLA-1 and Osteocalcin.
  • vitamin K is reduced to vitamin K hydroquinone (KH2) by the enzyme NADPH oxidase. It is only the reduced form of vitamin K that is able to function as a co-factor for gamma glutamate carboxylase (GGCX) which catalyzes the carboxylation of vitamin K dependent proteins. Warfarin blocks the generation of vitamin K hydroquinone by acting as a reductive sink.
  • GGCX gamma glutamate carboxylase
  • the enzymatic carboxylation of glutamate residues results in further oxidation of vitamin KH2 to 2-3 epoxide vitamin K ( Figure 2).
  • the final step of the vitamin k cycle requires the enzymatic oxidation of vitamin K 2-3 epoxide back to its native structure. This step is catalyzed by vitamin K oxidative reductase (VKOR) and is a component of the vitamin K cycle that is also blocked by the oxidative effects of Warfarin.
  • VKOR vitamin K oxidative reductase
  • Warfarin blocks both the generation of vitamin K hydroxyquinone (KH2) as well as the regeneration of Vitamin K22-3 epoxide helps to explains why the incidence of calciphylaxis and other forms of dystrophic calcification is higher among patients receiving Warfarin therapy.
  • the administration or supplementation of the disclosed compounds and compositions reduces the risk for vascular and soft tissue calcification by increasing the formation of primary calciprotein particles (CPP) composed of Fetuin A and Carboxylated Matrix GLA-1 Proteins.
  • CPP primary calciprotein particles
  • plasma calcium and phosphate concentrations are near supersaturation and thus would be expected to precipitate in blood vessels and soft tissue as crystalline hydroxyapatite.
  • This process does not occur suggests the presence of potent chemical and biologic means for blocking pathologic calcification.
  • Recent studies have shown that circulating calcium phosphate crystals are complexed with two calcification inhibiting proteins to form primary calciprotein particles (CPPs).
  • Matrix Gla-1 is a vitamin K dependent protein and early work by Price et. al and others have shown that formation of the Fetuin-Matrix Gla-1 mineral nanoparticles (primary calciproteins CPP) is dependent upon the gamma carboxylation of Matrix Gla-1.
  • primary calciproteins CPP primary calciproteins
  • the “absorption” of calcium- phosphate crystals by primary CCPs occurs in a coordinated and time-dependent process.
  • the time to 50% saturation (T 50 ) of primary CCPs is an accurate and highly sensitive means for determining the capacity of plasma to “sink” or “absorb” excess calcium phosphate crystals. Patients with a short T 50 times suggests a reduced capacity to absorb calcium phosphate crystals whereas patients with prolonged T 50 times are consistent with high capacities. Recent clinical studies have validated the T 50 test and confirmed that low T 50 times are associated with increased myocardial infarctions, heart failure and all-cause mortality. Thus, any clinical intervention that can increases the synthesis of circulating primary CCPs will improve the capacity to prevent pathologic calcification.
  • Vitamin K The regeneration of Vitamin K involves two key enzymes: vitamin K 2-3 epoxide oxidative reductase (VKOR) and NAD(P)H: quinone oxidoreductase (NQO1).
  • VKOR reduces 2-3 Vitamin K epoxide to vitamin K quinone while NADPH reduces Vitamin K quinone to its hydroxyquinone form (KH2).
  • VKORC-1 and VKORC 1 -Like-1 [VKORC1-L1] that differ in both enzymatic properties and tissue distribution. For example, Westhofen et.
  • VKOR-L1 is a specialized isoform that protects against oxidant injury through the regeneration of vitamin K.
  • H 2 O 2 When cultured HEK 293T cells were incubated with H 2 O 2 , VKOR-L1 expression was increased and evidence of membrane oxidant injury was reduced.
  • Casper et. al determined mRNA expression of key enzymes involved in regeneration of vitamin K.
  • the administration or supplementation or administration of the disclosed compounds and compositions will reverse hemodialysis induced inhibition of vitamin K dependent proteins through normalization of functional reduced forms of vitamin K.
  • oxidant conditions can disrupt the vitamin K cycle suggests that the oxidant load generated during hemodialysis could contribute to the high rates of vascular and soft tissue calcification observed within the ESRD population.
  • Work by Himmelfarb et al. and others have confirmed that the simply delivery of hemodialysis can lead to the oxidation of numerous tissue proteins. For example, hydroxyl amino acid side chains be oxidized to oxidized to carbonyl groups.
  • the oxidation of KH2 by hemodialysis block its ability to function as a co-factor for GGCX which down-stream leads to reduced gamma carboxylation of vitamin K dependent proteins.
  • the ratio of vitamin K quinone to 2-3 epoxide vitamin K and vitamin K hydroxyquinone (KH2) may be determined in patients with normal renal function, CKD (Stage IV & V) and ESRD patients.
  • CKD Serial IV & V
  • ESRD ESRD
  • Vitamin K are Vitamin K2.
  • the administration or supplementation with the disclosed compounds and compositions in ESRD patients with Calcific Uremic Arteriolopathy will reduce the time of wound healing by preventing calcification of new blood vessels and restoring blood flow: Skin Biopsies: To confirm that supplementation of the disclosed compounds and compositions prevents the development of small vessel calcification and dermal ischemia, we may identify patients with calciphylaxis confirmed by dermal skin biopsy and randomize patients to treatment with menaquinone-7 or placebo. Clinical Endpoints may include the following: 1) Time to Wound Vacuum therapy withdrawal and 2) time for wound healing defined as the time needed for a 50% reduction in collective the surface area of all calciphylaxis wounds.
  • the administration or supplementation with the disclosed compounds and compositions provides a significant increase in the bioavailability of the compounds, including menaquinone-9/menaquinol-9, and their mixtures, when compared to administration or supplementation.
  • the bioavailability increases by at least 5%, 10%, 15%, 20%, 30%, 40%, 50% or more, when compared to the administration or supplementation using menaquinone-9.
  • the administration or supplementation with the disclosed compounds and compositions provides a significant increase in the serum half life of the compounds, including menaquinone-9/menaquinol-9, and their mixtures, when compared to administration or supplementation.
  • the serum half life increases by at least 5%, 10%, 15%, 20%, 30%, 40%, 50% or more, when compared to the administration or supplementation using menaquinone-9.
  • Histopathologic Endpoints Comparison of Diagnostic dermal biopsy with Protocol repeat dermal biopsy after 12 weeks of Menaquinone-7 or Menaquinone-9 therapy. Change in the level of interstitial calcium deposition defined as the change in Von Kossa staining, which may be quantified by digital image color analysis. We may use dermal biopsies to validate the biomarkers at the tissue level. This process allows confirmation of the preventive properties of the disclosed menaquinol derivatives on early vascular calcification.
  • the supplementation of the disclosed compounds and compositions in ESRD patients with Calcific Uremic Arteriolopathy will reduce the time of wound healing by normalizing carboxy Protein C levels in the dermis and preventing primary thrombosis of dermal blood vessels. Accordingly, in one variation, the supplementation or administration of the disclosed compounds or compositions in diabetic patients will prevent the development of vascular dementia by preventing calcification and development of small vessel vasculopathy.
  • a fortified food or drink formulation comprising adding to the food or drink a composition comprising a compound of any one of the above compounds, or a mixture thereof.
  • compositions of the compounds of this invention may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulations are especially suitable for parenteral administration but may also be used for oral administration.
  • Excipients such as polyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride, or sodium citrate, may also be added. Alternatively, these compounds may be encapsulated, tableted, or prepared in an emulsion or syrup for oral administration.
  • Solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols, or water.
  • Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar, or gelatin.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing, and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, or an aqueous or non-aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • Suitable formulations for each of these methods of administration may be found in, for example, Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.
  • the disclosed compounds and compositions may include a solubility enhancer or solubilizer selected from oleic acid, Kolliphor® EL (polyoxyl castor oil or Cremophor EL), Vitamin E TPGS (D- ⁇ -tocopherol polyethylene glycol-1000 succinate), PEPI (a polysarcosine-derived emulsifying agent), Maisine® CC (glyceryl monolinoleate), Gelucire® 44/14 (lauroyl polyoxyl-32 glycerides), Miglyol® 812N (esters of saturated coconut and palm kernel oil-derived caprylic fatty acids and glycerin), Plurol® Oleique (Polyglyceryl-6 Dioleate), LauroglycolTM 90 (propylene glycol monolaurate (type II), Labrasol® (Caprylocaproyl polyoxyl-8 glycerides), Kolliphor® EL (polyoxyl castor oil), Captisol® (SBE-be
  • “Pharmaceutically acceptable salts” means salt compositions that is generally considered to have the desired pharmacological activity, is considered to be safe, non-toxic and is acceptable for veterinary and human pharmaceutical applications.
  • Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, malonic acid, succinic acid, malic acid, citric acid, gluconic acid, salicylic acid and the like.
  • "Therapeutically effective amount” means an amount of a compound or drug that elicits any of the biological effects listed in the specification.
  • Figure 1 is a representation of a chromatogram of menaquinone-7 and its regioisomer shown with a ratio of 3:1, as determined by 1 H NMR.
  • Figure 2 is a scheme showing the uremia and dialysis induced oxidation of KH2 functional carboxylation of vitamin K dependent proteins.
  • Figure 3 is graph showing the VKORC1 in arbitrary units and specific tissues.
  • Figure 4 is a graph showing the NADPH in arbitrary units and specific tissues.
  • Figure 5 is a graph showing CKD and ESRD patients exhibit a higher percentage of carbonyl proteins compared to normal controls.
  • EXPERIMENTAL [0081] The following procedures may be employed for the preparation of the compounds of the present invention.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methods well known to a person of ordinary skill in the art, following procedures described in such references as Fieser and Fieser's Reagents for Organic Synthesis, vols.1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd's Chemistry of Carbon Compounds, vols.1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols.1-40, John Wiley and Sons, New York, N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.
  • protective groups may be introduced and finally removed. Suitable protective groups for amino, hydroxy, and carboxy groups are described in Greene et al., Protective Groups in Organic Synthesis, Second Edition, John Wiley and Sons, New York, 1991. Standard organic chemical reactions can be achieved by using a number of different reagents, for examples, as described in Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989. Preparation of Menaquinol Derivatives: [0121] The menaquinol derivatives, such as the menaquinol-9 derivatives, may be prepared according to the general methods as described below.
  • Such acylated linked compounds may be symmetrical, wherein both hydroxyl groups of the menaquinol are acylated and linked to another menaquinol molecule, or only one of the two hydroxyl groups, either the 5-position or the 8-position, are acylated and linked to another menaquinol molecule, and the other remaining as the free hydroxyl group of the menaquinol.
  • reaction mixture was filtered through celite and washed with ethyl acetate (10 mL), filtrate was diluted with ethyl acetate (250 mL) and washed with water (2X100 mL), separated organic layer was concentrated and crude obtained was purified by column chromatography (3-4% ethyl acetate/hexane) to yield the compound IXa as a pale yellow liquid (75%).
  • the H 1 nmr obtained was consistent with the product.
  • the mono-acetate in step 1, 4-hydroxy-2-methylnaphthalen-1-yl acetate may be prepared by the reduction and subsequent di-acylation of 2-methyl-1,4-naphthoquinone using Pd/C, acetic anhydride, ethyl acetate and DMAP to form the diacylated quinol, which is then selectively de-acylated in methanol and ter-butylamine to provide the desired product, 4- hydroxy-2-methylnaphthalen-1-yl acetate.
  • reaction completion was monitored by TLC (15% ethyl acetate/hexane).
  • the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (2X100 mL). The organic layer was separated and washed with brine solution (50 mL) then dried over sodium sulfate and concentrated.
  • step 1 is in common with the preparation of the carbonate, as described above.
  • succinic anhydride 0.054 g, 0.54 mmol
  • DMAP 0.023 g, 0.18 mmol
  • the crude reaction was then loaded onto a packed silica column (25 mm x 152 mm) and filtered through the silica using two column volumes of hexanes, 1 column volume of 3.5% Et 2 O/hexanes, and four column volumes of 7% Et 2 O/hexanes, the latter of which was collected.
  • the organics were then evaporated into a 20 mL scintillation vial resulting in 869 mg of the ⁇ -allylated product, as a golden yellow oil which was carried over directly to the retro-Diels-Alder reaction.
  • Stability of the Compounds in SGF, FaSSIF and FeSSIF may be determined in Simulated gastric fluid (SGF, pH-1.2), Fasted state simulated intestinal fluid (FaSSIF, pH-6.5) and Fed state simulated intestinal fluid (FeSSIF, pH-5) at 0, 30, 60, 120 and 240 minutes. The % of compound disappearing over time may be calculated by comparing to peak areas of analyte at ‘0’ minute by HPLC/ LCMS analysis. Formation of the menaquinone, such as menaquinone-9 from the compounds tested, as disclosed herein, was observed.
  • a Table 3 noting the stability of the disclosed compounds as tested is determined in Simulated gastric fluid (SGF, pH-1.20), Fasted state simulated intestinal fluid (FaSSIF, pH-6.5) and Fed state simulated intestinal fluid (FeSSIF, pH-5) at 0, 30, 60, 120 and 240 minutes. The % of the compound disappearing over time was calculated by comparing to peak areas of analyte at ‘0’ minute by HPLC/ LCMS analysis. Formation of menaquinone-9 from the tested was observed. Stability in Human and Rat Plasma: [0146] A Table 4 noting the stability of the disclosed compounds as tested is determined in Human and Rat plasma (K 2 EDTA) at 0, 15, 30, 60 and 120 minutes.
  • K 2 EDTA Human and Rat plasma
  • Blood samples were collected at various time points during the next 48 hours post dose. [0152] Blood samples were collected and transferred to tubes containing K 2 EDTA and immediately placed on ice for plasma preparations.
  • Plasma was prepared by centrifugation at 3500 g for 10 min, aliquots were frozen at -80°C until analysis. Quantification of analyte in plasma was determined by LC-MS-MS analysis. Plasma PK parameters were calculated using WinNonlin software.
  • Administration of the Compounds in Subjects at Risk for Development of Calciphylaxis [0153] This example describes the administration of the compounds of the present application to subjects at risk for development of calciphylaxis, but who have not yet developed the characteristic skin lesions of calciphylaxis. Risk factors to be considered include, but are not limited to, diabetes mellitus, obesity, hemodialysis, and prior treatment with warfarin (Nigwekar et al.
  • the dosage form is a 10 mg, 20 mg, 50 mg or 100 mg soft-gel capsule.
  • Two 50 mg capsules are be administered once daily to the 100 mg dosage cohort. It should be noted that not all subjects with elevated risk factors for calciphylaxis will develop the characteristic skin lesions of calciphylaxis.
  • the intent of treating with the compound of the present application proactively (prior to a clinical diagnosis of calciphylaxis) is the prevention of lesion appearance. Thus, a drop in frequency of, or elimination of lesion appearances is contemplated to be a successful treatment.
  • biomarkers can be assessed to determine the efficacy of the compound to be administered at the three dose levels.
  • biomarkers include PIVKA-II; uncarboxylated and total Matrix Gla Protein (MGP); uncarboxylated, carboxylated and total osteocalcin protein; uncarboxylated, carboxylated and total Protein C, osteoprotegerin, Fetuin A and hs-CRP.
  • Blood samples are obtained to measure the biomarkers according to the following schedule. Blood sampling can occur during treatment on a weekly or monthly basis.
  • administering will result in (i) an increase in PIVKA-II, which is indicative of slowing the progression of, arresting, or reversing, calciphylaxis, (ii) a decrease in uncarboxylated MGP, uncarboxylated osteocalcin, and/or uncarboxylated Protein C, which is indicative of slowing the progression of, arresting, or reversing calciphylaxis.
  • pulse wave velocity PWV
  • Improved vascular compliance will be indicative of slowing the progression of, arresting, or reversing calciphylaxis.
  • the dosage form is a 5 mg, 10 mg, 25 mg, 50 mg or 100 mg soft-gel capsule. Two 50 mg capsules are administered once daily to the 100 mg dosage cohort.
  • the arrest of, or decreases in lesion size and frequency is contemplated to be an indication of successful treatment. The administration of the disclosed compounds according to the foregoing will result in the arrest of, or decrease in lesion size and frequency.
  • ESRD End Stage Renal Disease
  • This example describes the administration of the disclosed compounds to a subject with ESRD and on stable hemodialysis.
  • the administration of the disclosed compounds will result in a change in aortic compliance (via plethysmography), vascular calcification and certain biomarker levels indicative of slowing the progression of, arresting, or reversing tissue calcification.
  • ESRD subjects on stable hemodialysis orally receive the disclosed compounds at 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300, mg, 400 mg or 500 mg once daily for least 2 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 6 months, 1 year, or indefinitely.
  • the dosage form is a 5 mg, 10 mg, 25 mg, 50 mg, 75 mg or 100 mg soft-gel capsule. Two 50 mg capsules are administered once daily to the 100 mg dosage cohort.
  • a 50 y.o., 65 kg male patient diagnosed with the typical symptoms associated with moderate calciphylaxis is treated with 100 mg of the compound of the formula VIIIb for a period of 8 weeks. After the treatment period, the patient is admitted and evaluated.
  • a 65 y.o., 45 kg female patient diagnosed with the typical symptoms associated with moderate calciphylaxis is treated with 20 mg of the compound of the formula VIIIb, for a period of 10 weeks. After the treatment period, the patient is admitted and evaluated. The patient is found to have a significant change in the examined biomarker levels suggesting about a 20% reduction in vascular calcification, and is also shown to have a 15% reduction in tissue calcification.
  • a 55 y.o., 70 kg male patient diagnosed with the typical symptoms associated with moderate calciphylaxis is treated with 50 mg of the compound of the formula VIIIb, for a period of 3 months. After the treatment period, the patient is admitted and evaluated. The patient is found to have a significant change in the examined biomarker levels suggesting about a 25% reduction in vascular calcification, and is also shown to have a 20% reduction in tissue calcification.
  • Coronary arterial calcium scores are used to estimate the extent of calcification of thoracic arteries. A high CAC score is indicative of calcification, and treatment has the aim of arresting the long-term increase in CAC score, or reversing it, or slowing the rate of increase.
  • Aortic plethysmography also is used to measure arterial compliance, which decreases as calcification increases.
  • Pulse wave velocity (PWV) also is measured to assess arterial compliance. The foregoing measures are useful in estimating the utility of treatments intended to prevent, slow the progression of, arrest or reverse vascular calcification. These measurements are used pre- and post-treatment with the disclosed compounds to assess treatment value.
  • biomarkers are assessed to determine the efficacy of the disclosed compounds at the three dose levels.
  • biomarkers include PIVKA-II; uncarboxylated and total Matrix Gla Protein (MGP); uncarboxylated, carboxylated and total osteocalcin protein; uncarboxylated, carboxylated and total Protein C, and hs-CRP. Blood samples are obtained to measure the biomarkers, most conveniently during patient visits for hemodialysis.
  • MGP Matrix Gla Protein
  • osteocalcin protein uncarboxylated, carboxylated and total osteocalcin protein
  • hs-CRP hs-CRP.
  • the administration of the disclosed compounds can result in (i) an increase in PIVKA-II, which is indicative of slowing the progression of, arresting or reversing tissue calcification, (ii) a decrease in uncarboxylated MGP, uncarboxylated osteocalcin, and/or uncarboxylated Protein C, which is indicative of slowing the progression of, arresting or reversing tissue calcification, and/or (iii) a decrease in hs-CRP, which is indicative of slowing the progression of, arresting or reversing tissue calcification and/or reduced inflammation.
  • VKORC1L1 Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates vitamin K-dependent intracellular antioxidant function. J Biol Chem 2011;286: 15085–94.4) Caspers, M. et al., Two enzymes catalyze vitamin K 2,3-epoxide reductase activity in mouse: VKORC1 is highly expressed in exocrine tissues while VKORC1L1 is highly expressed in brain. Thrombosis Research 135:977–983, 2015.5) Himmelfarb, J. et al., Plasma protein thiol oxidation and carbonyl formation in chronic renal failure. Kidney International, Vol.58: 2571–25782000.6) Price, P.A.

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Abstract

La présente invention concerne, en partie, des dérivés de ménaquinol isolés, stables et biologiquement actifs et leurs méthodes d'utilisation pour le traitement de diverses maladies.
PCT/US2021/065401 2021-12-28 2021-12-28 Compositions de dérivés de ménaquinol biologiquement actifs et méthodes de traitement WO2023129141A1 (fr)

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